Antiepileptic Drugs, 5th Edition

Benzodiazepines

17

Chemistry, Biotransformation, and Pharmacokinetics

Gail D. Anderson PhD^*

John W. Miller MD, PhD^**

*Professor, Department of Pharmacy, University of Washington, Seattle, Washington

**Professor, Department of Neurology, University of Washington; and Director, Regional Epilepsy Center, Harborview Medical Center, Seattle, Washington

CLOBAZAM

Chemistry and Metabolic Scheme

Clobazam (7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione) is a benzodiazepine in which the imine group in the fourth and fifth position of the diazepine ring is substituted by an amide (Figure 17.1). It has a molecular weight of 301 and is a crystalline powder, which is relatively insoluble in water. Clobazam has marked antiepileptic properties (1), and it is said to be less sedating than other commonly used benzodiazepines (2,3). The primary metabolite of clobazam, N-desmethylclobazam, contributes significantly to the pharmacologic effect of clobazam, because it has higher serum levels than clobazam after administration (4).

Absorption

Bioavailability.

Clobazam is rapidly and completely absorbed (5); food has variable effects on this process (6). After a single 10-mg oral dose, a peak concentration of 164 to 325 ng/mL is reached in 0.5 to 2 hours (7) in healthy volunteers and in patients with epilepsy. After a 30-mg oral dose (8), peak levels of clobazam are reached in 1 to 3 hours, with a delayed peak of N-desmethylclobazam. Diurnal variation in absorption has been suggested (9).

Routes of Administration and Formulations.

Clobazam is not available for intravenous (i.v.) or intramuscular (i.m.) injection. Rectal solutions are initially absorbed more rapidly than capsules or suppositories, but they reach similar peaks of 200 to 400 ng/mL after doses of 30 mg (10). N-desmethylclobazam peaks in about 24 hours, with similar peak concentrations, time to peak, and area under the curve for oral capsules, rectal solution, and rectal suppositories (10). However, there is less variability in levels with rectal administration.

Distribution

Clobazam is highly lipophilic and is rapidly distributed in fat and in the brain, before being redistributed widely (11,12). It has a large volume of distribution (VD), measured at 81 ± 20 L in healthy subjects after a single oral 20mg dose (13).

Plasma Protein Binding.

Clobazam is about 85% protein bound (4). Hepatic disease decreases protein binding and approximately doubles VD relative to healthy subjects (13). A strong correlation exists between salivary and plasma concentrations of clobazam within a wide range of concentrations (14).

Cerebrospinal Fluid, Brain, and Other Tissues.

In preclinical studies, ¹⁴C-clobazam was found to distribute evenly in the brain and body tissues in rats and dogs without evidence of accumulation (12). However, at autopsy of a 6-year-old child who had received clobazam on a longterm basis, N-desmethylclobazam levels exceeded clobazam levels by 15-fold or more, and liver and brain levels exceeded those in serum (15).

Transplacental Passage.

Clobazam does cross the human placenta, and a neonatal withdrawal syndrome has been observed with prenatal exposure (16).

Breast Milk.

The ratio of milk to plasma for clobazam plus N-desmethylclobazam after 2 days of treatment is 0.13:0.36, with a maximal dose of 0.038 to 0.05 mg/kg/day to the child (17). It is suggested that the infant be monitored for signs of sedation. Based on the high protein binding of clobazam, infant exposure should be minimal, and breast-feeding is safe.

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FIGURE 17.1. Chemical structure of the benzodiazepines.

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Routes Of Elimination

Although eight metabolites of clobazam exist in humans, the active metabolite N-desmethylclobazam is the most important (12).

Biotransformation.

The main pathway is demethylation to N-desmethylclobazam, but hydroxylation also occurs. Unlike the 1,4-benzodiazepines, this hydroxylation occurs not at the 3 position of the heterocyclic ring, but at the 4 position before it is conjugated (12). This process leads to the formation of the other metabolites, 4-hydroxyclobazam and 4-hydroxydesmethylclobazam (18).

Renal Excretion.

Renal excretion of unmetabolized clobazam is not significant (19).

Clearance and Half-Life

Healthy Subjects.

The elimination half-life (t½) of clobazam ranges from 10 to 30 hours, whereas that of N-desmethylcobazam is 36 to 46 hours, thus accounting for its important contribution to the biologic action of clobazam (12).

Comedicated Epileptic Patients.

The pharmacokinetics of a 30-mg oral clobazam dose was compared between patients receiving long-term antiepileptic drug therapy and control subjects (8). Although absorption was similar, clobazam was more rapidly and completely metabolized in the comedicated patients, presumably because of induction of hepatic metabolism (Table 17.1). As a result of this, N-desmethylclobazam levels were higher in the patients. Because it has been shown that N-desmethylclobazam is an effective antiepileptic agent when it is directly administered (20,21), this metabolite appears to be primarily responsible for the antiepileptic effects of clobazam in comedicated patients. Another study also found increased N-desmethylclobazam:clobazam ratios in patients comedicated with carbamazepine, phenytoin, or phenobarbital (22,23).

TABLE 17.1. CLOBAZAM PHARMACOKINETICS. VALUES REPORTED AS MEAN ±STANDARD DEVIATION OR RANGE IN DIFFERENT POPULATION

Population Tmax (h) F V (L/kg) Fraction Bound (%) Half-life (h) Clearance (mL/min/kg) References Children — — 194 — 16 N-desmethylclobazam: 15 — 225 Adults: monotherapy 1.3-1.7 0.87 0.87-1.83 82-90 16.6-48.6 N-desmethylclobazam: 36-46 0.36-0.63 5, 6, 7,12,24 Elderly Male, 1.6 — Male, 1.4 Male, 86.5-90.4 Male, 47.7 Male, 0.36 24 Female, 1.5 Female, 1.83 Female, 85.0-89.2 Female, 48.6 Female, 0.48 Hepatic cirrhosis 2.5 — 178 — 51 — 13 Acute hepatitis 3.0 — 173 — 47 — 13 Tmax, time of peak concentration; F, bioavailability; V, volume of distribution.

Elderly Patients.

Study of the elimination of a single clobazam dose (24) revealed a statistically significant doubling of the t½ in elderly men (47.7 versus 16.6 hours), with trend toward a higher t½ in elderly women (48.6 versus 30.7 hours). The clearance is reduced (24).

Other Concurrent Conditions.

Hepatic disease may alter both protein binding and clobazam elimination, with a potentially profound effect on clobazam levels (4).

Relationship between Serum Concentration and Dose and Effect

Because of the active metabolite N-desmethylcobazam, no clear correlation exists between clobazam levels and effect (25, 26, 27). Studies relating N-desmethylcobazam levels to psychometrically measured effects have not been performed, but this metabolite has effects on γ-aminobutyric acid-mediated chloride currents in cultured neurons that are identical to those of a similar range of clobazam concentrations (28).

CLONAZEPAM

Chemistry and Metabolic Scheme

Clonazepam [5-(2-chlorophenol)-1,3-dihydro-7-nitro-2H-1,4 benzodiazepin-2-one] is a light yellow crystalline powder with a molecular weight of 315.7 and negative log of dissociation constant (pK_a) of 1.5 and 10.5 (Figure 17.1) (29).

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Absorption

Bioavailability.

After oral administration, the bioavailability of clonazepam was >80% in seven of eight healthy subjects (30). The time of peak plasma concentrations ranged from 1 to 4 hours (30,31). After rectal administration in adult patients (32) and six children (33), clonazepam was well absorbed and resulted in peak concentrations in 10 to 30 minutes but with substantial interindividual variation. Absorption of clonazepam after intranasal and buccal administration was compared with an i.v. bolus in seven healthy subjects (34). The bioavailability of both formulations was approximately 40%. The time to peak ranged from 15 to 30 minutes for the intranasal formulation and from 30 to 90 minutes for the buccal administration. The rate and extent of absorption of clonazepam were decreased in patients with higher than normal gastric pH who were treated with ranitidine compared with absorption in patients with a normal gastric pH who were treated with caffeine (35).

Routes of Administration and Formulations.

Clonazepam is available for oral administration as tablets and drops and as a parenteral formulation for i.v. administration.

Distribution

After i.v. administration, the distribution of clonazepam is described by a two-compartment model with a distribution t½ ranging from 0.7 to 3.4 hours (30). The VD ranges from 1.5 to 4.4 L/kg in healthy adults (30). In neonates, the apparent VD was similar to adults and ranged from 1.8 to 4.4 L/kg with a distribution t½ of 0.1 to 2.1 hours (36).

Plasma Protein Binding.

Clonazepam protein binding is 86% in healthy subjects and is slightly decreased in patients with liver cirrhosis or reduced renal function and before hemodialysis in patients with chronic uremia (37).

Cerebrospinal Fluid, Brain, and Other Tissues.

Studies in rodents have demonstrated that brain and plasma concentrations are proportional to dose with brain concentrations approximately three to four times higher than plasma (38).

Transplacental Passage.

Two case reports have described placental transfer of clonazepam. In a woman treated with clonazepam for 1 week before delivery, the umbilical arterial and venous plasma levels were approximately equal to the maternal plasma concentration at delivery (39). In another case report of a woman treated with clonazepam throughout her pregnancy, clonazepam concentrations in the umbilical cord blood were 60% of the maternal serum concentration at delivery. The infant suffered neonatal apnea within a few hours of birth, possibly because of clonazepam-induced respiratory depression (40).

Breast Milk.

After 12 days of breast-feeding, the infant described earlier had a serum clonazepam concentration of only 1 ng/mL, which could still be from the initial interuterine dose and not from breast milk specifically. Based on the high protein binding of clonazepam, infant exposure should be minimal, and breast-feeding should be safe.

Routes of Elimination

Biotransformation.

Clonazepam is extensively metabolized by reduction of the nitro group at the 7 position to form 7-amino-clonazepam and hydroxylated to form 3-hydroxyclonazepam (41); 7-amino-clonazepam is sequentially metabolized by acetylation to form 7-acetamido-clonazepam. Plasma concentrations of 7-amino-clonazepam are approximately equal to and tend to parallel those of clonazepam during long-term administration (42).

Genetics and Isozymes.

The initial reduction to 7-amino-clonazepam is catalyzed by the cytochrome CYP3A4 (43), and the subsequent acetylation occurs through N-acetyltransferase, which is polymorphically distributed (44). However, because the metabolite is not active, the genetic polymorphism is not clinically significant. The isozyme responsible for hydroxylation has not been identified.

Renal Excretion.

Less than 1% of the dose of clonazepam is excreted unchanged in the urine (31,42). In one study, urinary recovery of clonazepam and of its primary metabolites accounted for 41% to 61% after a single oral dose, and fecal recovery ranged from 8% to 31% (41). In this study, approximately 40% to 50% of the recovered dose consisted of 7-amino-clonazepam and 7-acetamido-clonazepam, with approximately 30% excreted as hydroxylated metabolites.

Clearance and Half-Life

Healthy Subjects.

The reported t½ and clearance of clonazepam range from 17 to 56 hours and 94 to 125 mL/hr/kg, respectively (30,31).

Comedicated Epileptic Patients.

Coadministration of clonazepam with drugs that induce or inhibit CYP3A4 will alter clonazepam plasma clearance. Phenobarbital and phenytoin significantly increase the clearance of clonazepam by 19% to 24% and 46% to 58%, respectively, with resulting decreases in clonazepam t½ (45). Clonazepam plasma concentrations decreased by 19% to 37% over 5 to 15 days after administration of carbamazepine (46). Coadministration of clonazepam with fluoxetine (47) or sertraline (48) did not alter clonazepam clearance in healthy subjects.

Children.

In a group of 18 neonates, the t½ ranged from 22 to 81 hours, with a prolonged t½ of 140 hours reported in one neonate (36) (Table 17.2). The corresponding clearance

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ranged from 25 to 150 mL/hr/kg. In a study of nine children ages 2 to 18 years, the oral clearance of clonazepam showed a ninefold variation and ranged from 7 to 64 mL/hr/kg, with a mean of 25 mL/hr/kg (49). In another study of four children ages 7 to 12 years, the oral clearance of clonazepam was 37 to 89 mL/hr/kg. The t½ ranged from 22 to 33 hours (50).

TABLE 17.2. CLONAZEPAM PHARMACOKINETICS

Population Tmax (h) F V (L/kg) Fraction Bound (%) Half-life (h) Clearance (mL/hr/kg) References Neonates — — 1.8-4.4 — 22-81 25-150 36 Children 2-3 — 2.1 ± 0.6 — 28 ± 4.6 53 ± 24 49,50 Adults: 1-4 >0.8 1.5-4.4 86 17-56 94-125 30,31 Monotherapy Polytherapy with inducers — — 2.3-7.7 87 12-46 96-208 45,46 Tmax, time of peak concentration; F, bioavailability; V, volume of distribution. Values reported as mean ± standard deviation or range in different populations.

Relationship between Serum Concentration and Dose

In children receiving clonazepam monotherapy, maintenance doses of clonazepam ranging from 0.028 to 0.11 mg/kg resulted in plasma concentrations of 13 to 72 ng/mL, with an excellent linear correlation between dose and serum concentration (50). In children receiving concurrent carbamazepine monotherapy, clonazepam doses of 0.03 to 0.18 mg/kg resulted in plasma concentrations of 13.8 to 67.9 ng/mL (51). A linear correlation between dose and serum concentrations has been demonstrated in adults, with doses of 1.2 to 2.9 mg/day dose resulting in serum concentrations of 4 to 36 ng/mL (52).

Relationship between Serum Concentration and Effect

In general, a clear relationship between serum concentration and effect has not been established. In children with absence seizures, efficacy was found with concentrations between 13 and 72 ng/mL (50). In patients with various epilepsy types, a clonazepam dose of 6 mg/day resulted in plasma concentrations of 25 to 30 ng/mL. On discontinuation of clonazepam in 14 patients, four patients who developed withdrawal symptoms had significantly higher 7-amino-clonazepam plasma concentrations than those without withdrawal symptoms but with similar clonazepam plasma concentrations (42). The significance of this observation is unknown.

CLORAZEPATE

Chemistry and Metabolic Scheme: Clorazepate dipotassium (7-chloro-1,3-dihydro-2-oxo-5-phenyl-1 H-1,4-benzodiazepine-3-carboxylic acid, monopotassium salt, monopotassium hydroxide) is a prodrug that is rapidly and completely decarboxylated to form desmethyldiazepam (DMD) (Figure 17.1). DMD is a major metabolite of other benzodiazepines including diazepam, chlordiazepoxide, and prazepam. Chemically, clorazepate is an off-white to pale yellow, fine, crystalline powder with a molecular weight of 408.93. It is soluble in water (100 and 200 mg/mL), ethanol (0.6 mg/mL), and isopropanol (0.7 mg/mL) and in organic solvents (<0.5 mg/mL) (53). At pH levels of <4, >90% of clorazepate is converted to DMD within 10 minutes (54).

Absorption

Bioavailability.

After oral administration, clorazepate is converted rapidly and completely in the stomach to DMD, and therefore the pharmacokinetics properties of clorazepate are described in terms of DMD. After oral administration of clorazepate, peak concentrations of DMD occur within 0.5 to 2 hours. The slow-release formulation, designed for once-daily administration, peaks in approximately 12 hours (55). Bioavailability of DMD after an oral or i.m. dose of clorazepate is approximately 90% to 100% (56,57). After either i.v. or i.m. administration, clorazepate decarboxylation to DMD is slower, with a chlorazepate elimination t½ of 2.3 to 2.4 hours (57). Because low gastric pH is required to convert clorazepate to DMD, any condition or medication that increases pH could alter the therapeutic efficacy of clorazepate. Administration of clorazepate with sodium bicarbonate at doses that increased the gastric pH to greater than 6 resulted in an increase in the time to peak serum concentrations and a decrease in the maximum serum concentration of DMD (58). However, studies in patients with a Billroth gastrectomy and impaired or absent gastric acid secretion did not demonstrate altered conversion of clorazepate to DMD (59). In some studies, coadministration with magnesia and alumina antacid suspension (60,61) reduced but did not significantly alter single-dose or steady-state DMD serum concentrations. Administration of clorazepate in patients after abdominal radiation resulted in a significantly decreased area under the concentration time curve for DMD compared with control subjects (62).

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Routes of Administration and Formulations.

Clorazepate is available as oral tablets, as capsules, as a slow-release preparation, and in some countries as a parenteral formulation that can be administered by i.v. or i.m. routes.

Distribution

After absorption, DMD distributes into the body in two phases, which can be characterized by a two-compartment model. The distribution t½ ranges from 0.7 to 2.2 hours. The VD ranges from 1 to 1.8 L/kg and is increased in obesity (56,63,64). Increasing age, female sex (65), and obesity (63) are associated with increased VD.

Plasma Protein Binding.

DMD is highly protein bound predominately to albumin (96% to 98%), and the extent of binding is decreased with decreasing albumin plasma concentrations (65,66).

Cerebrospinal Fluid, Brain, and Other Tissues.

Cerebrospinal fluid (CSF) concentrations of DMD correlate with its unbound serum concentrations and are approximately 4% of plasma concentrations (66). DMD rapidly crosses the blood-brain barrier. After long-term use of diazepam, DMD accumulates in the CSF (67). On autopsy in patients who had been treated with clorazepate or diazepam, DMD was concentrated in the adrenal gland, liver, and heart; intermediate concentrations were found in kidney, brain, and lung, and low concentrations were noted in skeletal muscle and fat (68).

Transplacental Passage.

In a study evaluating i.m. clorazepate in pregnant women during the first stage of labor, clorazepate crossed the placental barrier slowly (68), in contrast to DMD, which was transported rapidly across the placenta to the fetus. DMD showed excess accumulation in heart and lungs of the fetus when diazepam was administered (69).

TABLE 17.3. DMD PHARMACOKINETICS AFTER ADMINISTRATION OF CLORAZEPATE

Population Tmax (h) F V (L/kg) Fraction Bound (%) Half-life (h) Clearance (mL/min/kg) References Neonates 73-138 — 73 Adults: Monotherapy p.o.: 0.5-2 i.m.: 2.7-11 1.0 0.91 0.7-2.2 96-98 40-130 0.18-0.27 56,61, 65,72 Polytherapy with inducers p.o.: 0.5-1.5 — 1.63 ± 0.24 — 40.8 ± 9.96 0.47 ± 0.8 64 Elderly: Male p.o.: 0.5-4.0 — 0.8-1.6 — 50-219 0.06-0.23 65 Female 0.5-4.0 0.9-2.5 48-116 0.12-0.41 Obesity p.o.: 0.5-2.5 — 1.0-2.5 — 64-369 0.05-0.23 63 Pregnancy i.m.: 11 ± 2.2 — 3.1 ± 0.96 — 180 ± 100 0.37 ± 0.3 74 Tmax, time of peak concentration; F, bioavailability; V, volume of distribution; p.o., oral; i.m., intramuscular. Values reported as mean ± standard deviation or range in different populations.

Breast Milk.

DMD enters breast milk and reaches a concentration of 15% to 50% of the maternal plasma concentrations. However, the serum concentrations in the newborn are minimal.

Routes of Elimination

As stated earlier, clorazepate is a prodrug, which is rapidly converted to DMD in the stomach and is designed to produce therapeutic plasma concentrations of DMD.

Biotransformation.

DMD is excreted unchanged (5% to 9% of the dose), it undergoes sequential metabolism to a glucuronide conjugate (25%), or it is hydroxylated to oxazepam, a reaction catalyzed by CYP2C19 and CYP3A4 (50%) (70). (Temazepam is demethylated to oxazepam, which is eliminated unchanged, and as a glucuronide conjugate.)

Genetics.

See the later discussion of diazepam regarding CYP2C19 genetic polymorphism.

Biliary and Renal Excretion.

After oral administration, <1% of the dose is recovered in the urine as unchanged clorazepate. When given by either i.v. or i.m. routes, approximately 7% is recovered as unchanged clorazepate. Between 15% and 20% of the dose is recovered in the feces because of biliary secretion (53,71).

Clearance and Half-life

Healthy Subjects.

The t½ of DMD ranges from 55 to 100 hours, and clearance ranges from 0.18 to 0.27 mL/min/kg (56,61,65,72). In spite of the long t½, clorazepate is given in divided doses or as a slow-release formulation because of its rapid absorption, resulting in relatively high peak concentrations that have been associated with toxicity (Table 17.3). The t½ of DMD is prolonged in obese patients as a result of increased VD.

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Comedicated Epileptic Patients.

The t½ of DMD is reduced in patients who are comedicated with enzyme inducers, presumably because of increased clearance (64). Cimetidine increases the t½ of DMD by decreasing the clearance in both young and elderly subjects (72).

Children.

Neonates have a prolonged t½ (73).

Elderly Patients.

The t½ of DMD is increased and the clearance reduced in elderly men, but not in elderly women (65, 72).

Other Concurrent Conditions.

The t½ of DMD was prolonged in pregnant women because of an increased VD; however, there was no significant difference in clearance (74). The t½ was increased and the clearance was decreased in patients with liver disease (75). Smoking decreases the t½ and increases the clearance of DMD (76). Genetic variability in CYP2C19 is responsible for significant intersubject variability in clearance.

Relationship Between Serum Concentration and Dose and Serum Concentration and Effect.

After administration of clorazepate either by the oral or i.m. route, there is a two- to threefold range in DMD peak concentrations and area under the concentration time curve. Clorazepate is a prodrug and is inactive. The effect of clorazepate is the result of its active metabolites, DMD, temazepam, and oxazepam.

DIAZEPAM

Chemistry and Metabolic Scheme

Diazepam (7-chloro-1,3-dihyro-1 -methyl-5-phenyl-2H-1, 4 benzodiazepin-2-one) is a yellowish crystalline substance with a molecular weight of 284.8 and a melting point of 125° to 126°C (Figure 17.1). The pK_a of diazepam is 3.4. Diazepam is soluble in chloroform, ethanol, dioxane, and dilute hydrochloric acid, but it is not soluble in water (77).

ABSORPTION

Bioavailability.

On oral administration, 5-, 10-, or 20-mg doses of diazepam are rapidly and completely absorbed, with peak concentrations occurring within 30 to 90 minutes (78,79). Slow-release oral capsules peak in 3.8 hours; i.m. administration results in poor and irregular absorption, with plasma levels only approximately 60% of those obtained after oral administration (80,81). Rectal administration of a 0.5 to 1.0 mg/kg diazepam solution results in peak concentrations within 60 minutes (82,83). A rectal gel formulation is rapidly and completely absorbed within 30 to 60 minutes after rectal administration with an estimated absolute bioavailability of 90% (84). Diazepam rectal suppositories exhibit slow and variable absorption and are not suitable for the treatment of acute seizures (82,85).

Routes of Administration and Formulations.

Diazepam is administered by oral, i.v., i.m., and rectal routes and is available as an oral solution, tablets, a sustained-release capsule, a rectal suppository and gel, and a parenteral formulation.

Distribution

After i.v. administration, diazepam distributes into the body in two phases, which can be characterized by a two-compartment mathematical model. Diazepam distributes quickly into lipoid tissues and rapidly crosses the blood-brain barrier (86). The VD ranges from 1 to 2 L/kg (87). Female patients have a larger VD (1.87 L/kg) than male patients (1.34 L/kg) (88). Elderly persons have a larger VD (1.4 L/kg) than young persons (0.88 L/kg) (89). There is no significant difference in the VD in neonates, infants, or children (87).

Plasma Protein Binding.

Diazepam is highly protein bound, and binding is significantly related to albumin, α₁-acid glycoprotein, and free fatty acid concentrations (90). Protein binding ranges from 97% to 99% (75,86). Protein binding is decreased in patients with reduced liver cirrhosis (75), in acute and chronic renal failure (91, 92, 93), in the elderly (93), and in the fetus and newborn (69). By the end of the first week, protein binding reaches adult levels, paralleled by changes in free fatty acid concentration (94,95).

Cerebrospinal Fluid, Brain, and other Tissues.

The CSF concentrations of diazepam and DMD correlate with unbound concentrations (2% and 4% of plasma concentrations, respectively) (66). After an i.v. dose of diazepam, the time of onset in patients with status epilepticus ranges from immediate effect to 10 minutes (median, 2 minutes), a finding suggesting a rapid distribution into brain (96). Animal studies have demonstrated that brain concentrations of diazepam are obtained rapidly after i.v. administration and then decline in parallel to changes in plasma concentrations (97). Diazepam was concentrated in the adrenal gland, liver and heart, and kidney with lower concentrations in lung, fat, and brain at autopsy in patients who had been treated with diazepam (98).

Transplacental Passage.

Both diazepam and DMD distribute across the placenta. DMD accumulates in fetal heart and lung (69).

Breast Milk.

Because of the extensive protein binding of diazepam and DMD, the ratio of milk to plasma is low, ranging from 0.1 to 0.5, so the infant receives <5% of the

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therapeutic pediatric dose (99). However, during prolonged treatment with diazepam, the infant should be observed for signs of excess sedation.

Routes of Elimination

Biotransformation.

Diazepam is extensively metabolized to several active metabolites including DMD, temazepam, and oxazepam (100). DMD is formed by a demethylation reaction catalyzed by CYP2C19 (major) and CY3A4 (70). DMD accumulates in blood to concentrations severalfold higher than diazepam. DMD is hydroxylated to oxazepam, a reaction catalyzed by CYP2C19, which is either excreted unchanged or undergoes sequential metabolism to a glucuronide conjugate. Diazepam is also hydroxylated to temazepam, a reaction catalyzed by CYP3A4 (70). Temazepam is demethylated to oxazepam or is excreted unchanged.

Genetics.

Diazepam and DMD pharmacokinetics has been studied in subjects phenotyped for the CYP2C19 polymorphism. In a study in groups of poor and extensive metabolizers of CYP2C19, (101) the mean t½ of DMD was significantly longer in poor metabolizers of CYP2C19 (161 hours) than extensive metabolizers (116 hours). The mean t½ of diazepam was approximately the same in the Chinese extensive metabolizers of CYP2C19 (85 hours) and poor metabolizers (88 hours) but twice that of whites, who were extensive metabolizers (40.8 hours). A study in Korean patients (102) found the t½ of both diazepam (59.7 versus 91.0 hours) and DMD (95.9 versus 213.1 hours) to be significantly shorter in extensive metabolizers of CYP2C19 compared with poor metabolizers. Similar results were found in a group of white patients who were poor and extensive CYP2C19 metabolizers (103).

TABLE 17.4. DIAZEPAM AND DMD PHARMACOKINETICS AFTER DIAZEPAM ADMINISTRATION

Population Tmax (h) F V (L/kg) Fraction Bound (%) Half-life (h) Clearance (mL/min) References Neonates/infants — — 1.3 ± 0.2 Neonate: 84 Newborns: D: 31 ± 2 Infants: 10 ± 2 — 226 Children p.o.: 30-90 i.m.: 30-60 Rectal gel: 10-30 — 2.6 ± 0.5 — D: 17 ± 3 DMD: — 100 Adults: p.o.: 30-90 1.0 0.95-2.0 D: 96-99 D: 28-54 D: 15-35 78,79 Monotherapy i.m.: 30-60 Rectal gel: 10-30 DMD: 97 DMD 7.4-11.3 Polytherapy with inducers — — — D: 36 ± 5 D: 18.7 ± 2.3 104 DMD: 1.6 DMD: 35.8 ± 7.4 Elderly — 1.0 0.8-2.2 94.2 ± 0.38 D: 80-100 DM: 151 ± 60 D: 10-32 DM: 4.3 ± 1.5 89 Hepatic disease — — 0.6-1.7 95.3 ± 1.8 D: 59-116 h DMD: 108 ± 40 D: 8-24 DM: 4.6 75,104 Renal disease — — — 92.0 ± 7.7 — D: 28 ± 10 91, 92, 93 Pregnancy — — — — D: 65 ± 29 — 69 Tmax, time of peak concentration; F, bioavailability; DMD, desmethyldiazepam; V, volume of distribution; D, diazepam; p.o., oral; i.m., intramuscular. Values reported as mean ± standard deviation or range in different populations.

Biliary and Renal Excretion.

Diazepam is not excreted into the bile in significant amounts (75). Only a small percentage (2% to 3%) of diazepam is excreted unchanged in the urine (89).

Clearance and Half-Life

Healthy Subjects.

The t½ of diazepam is approximately 1 to 2 days and is independent of dose (Table 17.4). DMD has a significantly longer t½ of 3 to 4 days and will accumulate, reaching two to five times higher concentrations at steady state than diazepam. Mean plasma clearance ranges from 14 to 35 mL/min in extensive metabolizers of CYP2C19 and from 9 to 12 mL/min in poor metabolizers of CYP2C19.

Comedicated Epileptic Patients.

Patients comedicated with hepatic enzyme-inducing drugs (carbamazepine, phenytoin, phenobarbital, primidone) have a decreased t½ of diazepam and DMD (104).

Children.

Neonates and infants have decreased hydroxylation and glucuronidation capacity, which may result in a decreased clearance of diazepam (105).

Elderly Patients.

There is no age-related difference in diazepam clearance after single or multiple doses (89).

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Other Concurrent Diseases.

Clearance is decreased, and t½ of DMD is significantly increased in patients with acute viral hepatitis and alcoholic cirrhosis when diazepam is administered (75,104).

Relationship between Serum Concentration and Dose

Diazepam plasma concentrations vary up to 10-fold after a single oral dose, threefold after multiple oral doses, and severalfold after i.v., i.m., and rectal administration (77,87).

Relationship between Serum Concentration and Effect

After multiple doses of diazepam, the pharmacologic effect of diazepam results from a combination of the effects of diazepam, DMD, temazepam, and oxazepam. In contrast, after a single dose of diazepam, metabolite accumulation does not occur to the extent of providing an initial effect; however, the prolonged t½ of DMD contributes to the duration of effect (77,87).

LORAZEPAM

Chemistry and Metabolic Scheme

Lorazepam (7-chloro-5(2-chlorophenyl)-1,3-dihydro-3-dihyroxy-2H-1,4-benzodiazepine-2-one) is a white, odorless, crystalline powder with a molecular weight of 321.16 and a melting point of approximately 168°C (Figure 17.1). It has pK_a values of 1.3 and 11.5 and is virtually insoluble in water and undissociated at physiologic pH (106).

Absorption

Bioavailability.

After oral administration in six healthy subjects, the bioavailability of lorazepam was >90%, with the time of peak concentrations within 1 to 2 hours (107,108). After i.m. administration of lorazepam, peak concentrations occur with 1 to 2 hours, and bioavailability is >90%. Sublingual administration of lorazepam resulted in a time lapse before absorption of approximately 23 minutes in nine of 10 subjects. The mean absorption t½ was 29 minutes, and bioavailability was 98% (108).

Routes of Administration and Formulations.

Lorazepam is available as oral and sublingual tablets and as a parenteral solution for i.v. and i.m. administration.

Distribution

After both i.v. and i.m. administration, the distribution of lorazepam is described by a two-compartment model with a distribution t½ ranging from 1 to 30 minutes (107,108). The VD ranges from 0.85 to 1.5 L/kg in healthy subjects (108,109). In critically ill neonates, the VD is approximately the same as in adults. In a study of 15 healthy elderly subjects, the VD was slightly less (0.99 L/kg) compared with young subjects (1.1 L/kg) (110). The VD in obese patients is significantly larger than in normal-weight controls. When normalized for body weight, there is no significant difference (111). In patients with liver cirrhosis, the VD was significantly increased compared with healthy subjects because of decreased protein binding (112).

Plasma Protein Binding.

Lorazepam is approximately 93% protein bound to albumin, and binding is independent of concentration (113) and sex (114). Protein binding is decreased in the elderly (88%) (114) and in patients with concurrent liver disease (87%) (112).

Cerebrospinal Fluid, Brain, and other Tissues.

Approximately 10% to 15% of the corresponding plasma concentration of lorazepam is found in the CSF; that this is approximately equal to the unbound fraction suggests that passage into the CSF is passive (115). Transport of lorazepam into CSF has been investigated in rodent (116) and mammalian models (117). In rats, lorazepam accumulates in brain tissue to concentrations approximately 40 times unbound concentrations in the serum, a finding suggesting that lorazepam is bound to receptors in the brain (116). In a study comparing i.v. lorazepam with diazepam in healthy subjects, the electroencephalographic effect did not reach maximum until 30 minutes after infusions of either low or high doses of lorazepam compared with 2.5 minutes with diazepam (118). In a follow-up study, the t½ for equilibration between plasma and the brain was 0.15 hour (119).

Transplacental Passage.

Lorazepam distributes readily into the placenta (120, 121, 122). Single i.v. doses of lorazepam during labor result in approximately equal plasma concentrations in the infant at birth (121). A large study of 53 neonates born to 51 mothers receiving lorazepam demonstrated that umbilical cord blood concentrations were slightly lower than maternal plasma concentrations at time of delivery. Three-fourths of the infants requiring ventilation at birth had cord lorazepam concentrations >45 ng/mL (122).

Breast Milk.

Because of its high protein binding, transfer of lorazepam into breast milk is minimal, and breast-feeding should be safe.

Routes of Elimination

Biotransformation.

Lorazepam is extensively metabolized by the liver to a glucuronide conjugate at the 3-hydroxy position, a reaction catalyzed by uridine diphosphate glucuronosyltranferase.

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Minor metabolism also includes a 2-quinazoline carboxylic acid and hydroxylorazepam (123). Plasma concentrations of lorazepam glucuronide are twice as high as those of lorazepam (124). The glucuronide metabolite is inactive and does not contribute to the pharmacologic effect of lorazepam (123).

Biliary and Renal Excretion.

Less than 1% of lorazepam is excreted unchanged by the kidneys (107,124). Approximately 75% of the lorazepam dose is recovered as lorazepam glucuronide, with 13% recovered as minor metabolites (123). After administration of ¹⁴C-lorazepam to healthy subjects, 88% of the dose was recovered, with 78% as lorazepam glucuronide, and fecal recovery accounted for only 7% (124). Lorazepam undergoes significant enterohepatic recirculation. When enterohepatic recirculation was interrupted by administration of neomycin and cholestyramine, lorazepam oral and systemic clearance increased by 34% and 24%, respectively (125).

Clearance and Half-Life

Healthy Subjects.

The clearance and t½ of lorazepam have been determined in numerous studies with various dosage forms. The ranges of clearances and t½ are 0.91 to 1.75 mL/min/kg and 17 to 56 hours, respectively (107, 108, 109, 112,118,222). A slight decrease in clearance with a 3-mg i.v. dose (1.88±0.23 mL/min/kg) compared with a 1.6-mg i.v. dose (2.08±0.22 mL/min/kg) has been reported (118). In contrast, pharmacokinetic studies of three patients who took overdoses of lorazepam found that the t½ of lorazepam was approximately the same as was found with therapeutic doses, a finding suggesting non-dose-dependent elimination (126).

Comedicated Epileptic Patients.

Even though lorazepam is commonly used in patients who are also receiving other enzyme-inducing antiepileptic drugs, there are no pharmacokinetic studies in this patient population (Table 17.5). Based on the hepatic induction profile of carbamazepine, phenytoin, and phenobarbital, lorazepam clearance should be significantly increased and t½ decreased with concurrent use of hepatic enzyme inducers. Valproate decreases the clearance of lorazepam by approximately 40% (127).

TABLE 17.5. LORAZEPAM PHARMACOKINETICS

Population Tmax (h) F V (L/kg) Fraction Bound (%) Half-life (h) Clearance (ml/min/kg) References Neonates — — 0.76 ± 0.37 — 40.2 ± 16.5 0.232 ± 0.11 128 Children — — 0.8 ± 0.06 — 7.7-17.3 0.8 ± 0.08 129 Adults: Monotherapy 107-109,112,118,227 p.o.: 2.4 ± 0.3 0.99 ± 0.06 0.85-1.5 93.2 ± 1.8 7-26 0.91-1.76 i.m.: 1.2 ± 0.3 s.l.: 2.3 ± 0.7 0.96 ± 0.04 0.94 ± 0.07 Elderly i.m.: 1.03 ± 0.16 p.o.: 0.95 ± 0.19 — 0.99 ± 0.03 87-89 15.9 ± 1.1 0.77 ± 0.06 110,114 Obesity — — 1.25 ± .10 89.1 ± 0.4 16.5 ± 1.7 0.98 ± 0.12 111 Hepatic cirrhosis — — 2.01 ± 0.82 88.6 ± 2.5 41.2 ± 24.5 0.81 ± 0.48 112 Acute hepatitis — — 1.52 ± 0.64 91.0 ± 1.9 28.3 ± 8.9 0.74 ± 0.34 112 Cystic fibrosis — — 1.5 ± 0.1 — 6.9-17.3 1.8 ± 0.2 129 Tmax, time of peak concentration; F, bioavailability; V, volume of distribution; p.o., oral; i.m., intramuscular; s.l., subcutaneous. Values reported as mean ± standard deviation or range in different populations.

Children.

Neonates receiving lorazepam by maternal transmission at birth cleared lorazepam slowly. Full-term infants continued to excrete lorazepam for at least 8 days, and preterm infants excreted the drug for at least 11 days (122). The clearance was approximately 25% of that found in adults, with a resulting prolonged t½ in critically ill neonates receiving i.v. lorazepam (128). In a study designed to evaluate the effects of cystic fibrosis, the control group consisted of children and adolescents ages 7 to 19 years. There was no significant difference in the pharmacokinetics of lorazepam compared with adult values taken from the literature (129). There is no information on the pharmacokinetics of lorazepam in infants and children ages 1 to 7 years. Because glucuronidation reaches adult levels by ages 2 to 3 years (130), after the age of 3 years, clearance corrected for body weight should be approximately the same as for adults. In infants and children <3 years old, doses should be reduced because of a decreased glucuronidation capacity and presumably decreased clearance.

Elderly Patients.

Lorazepam clearance was slightly reduced by 22% in a group of 15 elderly healthy subjects compared with young subjects. There was no difference in t½ (110).

Obesity.

In one study, the clearance of lorazepam was increased in obesity; however, as with the VD, when normalized for body weight, no significant difference was noted (111). Therefore, there was no resulting difference in t½.

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Other Concurrent Conditions.

There is no significant difference in the pharmacokinetics of lorazepam in patients with acute hepatitis (112). In contrast, liver cirrhosis is associated with an increase in the VD of lorazepam resulting in a doubling of the mean t½. Because of the lack of renal excretion of unchanged drug, the clearance of lorazepam is unaffected by renal impairment. Only 8% of lorazepam is removed by 6 hours of hemodialysis (131). There was no difference in the pharmacokinetics of lorazepam between patients with well-controlled insulin-dependent diabetes mellitus and healthy controls (132). In a group of patients with cystic fibrosis, the clearance of lorazepam was approximately double, and t½ was 50% compared with an age-matched control population (129). Lorazepam clearance was decreased by 37%, and t½ was increased in a group of tetraplegic patients compared with healthy subjects. The clearance in paraplegic patients was decreased, although not to the same extent as in the tetraplegic patients (133).

Relationship between Serum Concentration and Dose

The relationship between dose and serum concentration for all routes of lorazepam administration is linear. Oral doses of 2 or 4 mg of lorazepam result in peak plasma concentrations of 23 to 36 µg/mL or 39 to 68 µg/mL, respectively (107,108). For multiple doses, plasma clearance varies twofold, which will result in a corresponding twofold variation in steady-state plasma concentrations.

Relationship between Serum Concentration and Effect

A study in patients with intractable partial complex seizures suggested a narrow therapeutic range of 20 to 30 ng/mL for seizure control, with side effects occurring at concentrations >33 ng/mL (134). Lorazepam plasma concentrations of 30 to 100 ng/mL resulted in good seizure control in a group of patients with status epilepticus (135). A pharmacokinetic-pharmacodynamic study of the amnesic effects of lorazepam found a 50% effective concentration of 12 to 15 ng/mL (136).

MIDAZOLAM

Chemistry and Metabolic Scheme

Midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine) is an imidazobenzodiazepine that readily forms soluble salts (pK_a 6.15) because of the nitrogen in position 2 or the imidazole ring (137,138). It has a molecular weight of 362 (Figure 17.1) (137).

Absorption

Bioavailability.

Midazolam is administered parenterally as a salt in an acidic aqueous solution. However, at physiologic pH, it is highly lipophilic. As a result, it has very rapid onset and a short duration of action after single i.v. or i.m. doses. Peak sedation is achieved within 3 minutes in healthy adults after i.v. infusion (138). Midazolam is compatible with 5% dextrose in water, normal saline, and lactated Ringer's solution.

Routes of Administration and Formulations.

Midazolam is commonly used as a midazolam hydrochloride solution at acidic pH (3.3 to 3.5). Midazolam can be administered intermittently or continuously by the i.v. or i.m. route. Because parenteral formulations do not require propylene glycol or other lipoidal substituents, local irritation from injections are minimal. After i.m. injection, peak levels are reached in 20 to 30 minutes, with 91% bioavailability for midazolam hydrochloride (138). The parenteral formulation has been administered by the oral, rectal, buccal, (139,140) and intranasal (141,142) routes; an oral tablet is available in Europe, and an oral syrup is available in the United States. Testing of the oral midazolam syrup indicates that when 1 mg/kg is administered as an oral syrup (143), adequate sedation is produced within 30 minutes. However, because midazolam is rapidly cleared by the liver, only about half of an orally administered dose reaches the systemic circulation as unchanged drug (144). In children, oral bioavailability is as low as 27% because of first-pass hepatic metabolism (145).

Distribution

After i.v. administration, midazolam has a rapid phase of disappearance because of distribution, with a t½ of 6 to 15 minutes (144), followed by slower disappearance resulting from biotransformation. In healthy subjects, the VD is 1 to 2.5 L/kg (146, 147, 148, 149, 150, 151, 152), and it increases with obesity (153) and in the elderly (154,155).

Plasma Protein Binding.

The plasma binding of midazolam is 97% (137).

Cerebrospinal Fluid, Brain, and other Tissues.

In experimental animals, midazolam has been shown to equilibrate between plasma and CSF within a few minutes of i.v. administration and then to enter cerebral tissue rapidly (117).

Routes of Elimination

Midazolam is rapidly eliminated by hepatic and intestinal metabolism, a reaction catalyzed entirely by CYP3A4, with a hepatic extraction ratio of 0.3 (156).

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Biotransformation.

Metabolism occurs by oxidation of the imidazole ring, predominately to 1-hydroxymidazolam (75%), with small amounts of 4-hydroxymidazolam (3%) and 1,4-dihydroxymidazolam (1%) (157, 158, 159, 160, 161). This is followed by glucuronidation. The main metabolite, 1-hydroxymidazolam, has about 10% of the biologic activity of midazolam and an elimination t½ of 1 hour (146,161).

Genetics.

Midazolam metabolism entirely depends on CYP3A, and its hepatic clearance has been used as a phenotyping probe for this cytochrome P450 enzyme subfamily (156,162). A higher proportion of isoform CYP3A5 favors production of 1-hydroxymidazolam, whereas 1,4-hydroxyl production is favored when more CYP3A4 is present (163, 164, 165). Although considerable individual variation in these isoforms exist, clinically significant differences have not been found between African-American and European-American populations (166).

Renal Excretion.

Approximately 45% to 57% of midazolam is renally excreted as glucuronide conjugates, with only 0.03% of midazolam excreted unchanged (137).

Clearance and Half-Life

Healthy Subjects.

The t½ of midazolam ranges from 1.5 to 4 hours, and clearance ranges from 0.24 to 0.53 L/min (146,148,149).

Comedicated Epileptic Patients.

Midazolam metabolism is decreased by drugs that inhibit the activity of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, diltiazem, verapamil, and cimetidine (149,167,168) (Table 17.6). Long-term administration of agents such as carbamazepine, phenytoin, and barbiturates, which induce hepatic metabolism, decrease midazolam bioavailability appreciably.

TABLE 17.6. MIDAZOLAM PHARMACOKINETICS

Population Tmax (h) F V (L/kg) Fraction Bound (%) Half-life (h) Clearance (mL/min/kg) References Neonates — — — — 6.52-12 3.9-6.85 169,170 Children — — — — 0.78-2.4 6.4-15.4 145,171,172 Adults: monotherapy i.m.: 0.24-0.51 p.o.: 0.5-0.97 i.v., i.m.: 1.0 p.o.: 0.40 0.7-1.7 96 1.36-4 6.4-11.1 144, 147, 148, 149,151,161,179 Elderly Male, 0.71-0.85 — Male, 119-139 — Male p.o.: 3.43-5.35 i.v.: 4.2-7.0 Male, 296-382 153 Female, 0.54-0.74 Female, 113-137 Female p.o.: 2.65-4.55 i.v.: 3.2-4.8 Female, 383-481 Obesity 0.77-1.01 — 284-338 — i.v. 7.56-9.24 p.o.: 5.09-6.79 434-510 mL/min 153 Chronic renal failure — — 3.48-4.1 — 3.83-5.33 9.85-12.95 176 Tmax, time of peak concentration; F, bioavailability; V, volume of distribution; i.m., intramuscular; i.v., intravenous; p.o., oral. Values reported as mean or range in different populations.

Children.

In neonates, the t½ of midazolam is prolonged, with a decreased clearance compared with adults (169,170). The t½ of midazolam is somewhat shorter in children, and the clearance is somewhat higher (137,145,171,172).

Elderly Patients.

In these patients, the midazolam VD may be increased, and the t½ may be prolonged (154, 155).

Other Concurrent Conditions.

The clearance of midazolam is reduced in patients with hepatic disease (173), congestive heart failure (174), and decreased cardiac output or hepatic blood flow (175). Renal failure increases the free fraction of midazolam because of reduced plasma protein binding; one study found that it did not significantly affect midazolam elimination (176), although another found prolongation of the t½ to 13 hours in patients with renal failure who were in an intensive care unit (177).

Relationship between Serum Concentration and Dose and Effect

A good relationship has been found between midazolam plasma or serum concentration and psychometrically measured effects after oral (149,178), i.m. (179), and i.v. (149,178, 179,180) administration. Subjective effects occur at a threshold of levels of 30 to 100 ng/mL (149,178,179).

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NITRAZEPAM

Chemistry and Metabolic Scheme

Nitrazepam (1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one) is a benzodiazepine derivative (Figure 17.1) that is used as a sedative-hypnotic agent (181,182) and to treat selected forms of epilepsy in some countries (183, 184, 185, 186). It is a yellow, odorless, tasteless crystalline powder, which is insoluble in water, but soluble in chloroform, ethanol, ether, and diluted inorganic acids. It has a molecular weight of 281.3 and a melting point of 226° to 229°C. It has pK_a values of 3.2 and 10.8 (187).

Absorption

Bioavailability.

Mean peak plasma concentrations of 35 to 47 ng/mL are reportedly achieved after an oral dose of 5 mg of nitrazepam, and levels of 83 to 164 ng/mL occur after 10-mg doses both in healthy young and elderly patients of both sexes. Peak levels are usually achieved in less than an hour (188, 189, 190, 191, 192, 193, 194). Rectal administration leads to similar peak levels in approximately 18 minutes (191).

Routes of Administration and Formulations.

Nitrazepam is administered by oral, i.v., i.m., and rectal routes. Oral bioavailability is reportedly total with oral administration (191), but it is only 80% when the drug is given rectally. There is some evidence that peak level times vary among different oral preparation brands (189).

Distribution

The distribution of nitrazepam can be explained in a two-compartment open model either after i.v. administration or after the peak concentration has been reached (187, 188, 189,191,195,196). The initial rapid decline of concentration resulting from redistribution has a t½ of 17 minutes. The mean VD in young healthy subjects is 2.0 L/kg (191,196) after i.v. administration and 2.4 L/kg after oral administration (197). One study (198) found no gender differences; another (194) found a larger VD in women (2.56 versus 1.82 L/kg). Elderly subjects have a somewhat larger VD than young subjects (194,197,199), although this difference is small at steady state (199).

Plasma Protein Binding.

Nitrazepam is highly protein bound, with an 85.8% to 86.8% bound fraction (184). Protein binding is decreased in patients with hepatic cirrhosis (81.1% versus 86.2% in healthy controls) (199), but VD is unaffected. Similarly, binding is also decreased in patients with chronic renal insufficiency (83.2% versus 85%) (200). Protein binding in healthy elderly patients is similar to that in young subjects (194,201).

Cerebrospinal Fluid, Brain, and Other Tissues.

Evidence suggests that equilibration between plasma and CSF concentrations occurs slowly (202), because after a 5-mg oral dose, the percentage ratio of CSF to plasma concentrations increases from 8% at 2 hours to 15.6% at 36 hours. Animal studies have found a brain to plasma concentration ratio of 60% at 15 to 30 minutes after i.v. administration (203), but brain concentrations are lower in younger rats (204). Excretion of nitrazepam into saliva is variable and does not reliably reflect free plasma concentration (197, 205,206). On postmortem examination of patients who had taken nitrazepam on a long-term basis, similar concentrations of nitrazepam were present in peripheral blood and in the liver, but nitrazepam was concentrated in the vitreous humor and bile (207). Significant redistribution did not occur after death (207).

Transplacental Passage.

Nitrazepam does cross the human placenta, with lower concentrations than plasma early on, but with equilibrium with maternal tissues in late pregnancy (208).

Breast Milk.

Nitrazepam is excreted into breast milk only in low concentrations (184,209,210). However, sedation has nonetheless been reported in nursing infants of mothers who take nitrazepam (211).

Routes of Elimination

Nitrazepam elimination is primarily urinary and is independent of dose and administration route (184,187).

Biotransformation.

Nitrazepam undergoes nitroreduction, which is mediated not only by hepatic enzymes but also by intestinal microflora (212). Subsequent acetylation to 7-aminonitrazepam and the hydroxylation of a small fraction of this metabolite occur in the liver (184,213,214). A secondary metabolic route to benzophenones also exists (187).

Genetics.

The acetylation of 7-aminonitrazepam is genetically polymorphic, but this is not clinically significant because 7-aminonitrazepam is not pharmacologically active (215,216).

Biliary and Renal Excretion.

About half of a single oral dose of nitrazepam is excreted in the urine within a week (184,217). Most of this is in the form of the metabolites 7-acetamidonitrazepam and 7-aminonitrazepam, with less than 1% unchanged. Nitrazepam and its metabolites are found in bile at five to 12 times plasma concentrations (36,207), and 8% to 20% of nitrazepam doses are excreted in the feces (217).

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TABLE 17.7. NITRAZEPAM PHARMACOKINETICS

Population Tmax (h) F V (L/kg) Fraction Bound (%) Half-life (h) Clearance (mL/min/kg) References Neonates — — 85-88 — — 197 Adults: monotherapy 1.35-2.47 0.54-0.93 2.5-2.9 85-88 21-40 1.51-1.91 184,188,195,197,228,229 Elderly 4-8 — 3.1-6.5 — 24.2-56.6 — 220,228 Obesity — — 2.45-2.79 79.9-80.7 31.3-35.7 — 193 Hepatic Cirrhosis — — 2.17 81.1 30.5 59 mL/min 199 Chronic renal failure — — 3.84-4.48 83.2 20.4-42.6 1.9-6.5 200 Tmax, time of peak concentration; F, bioavailability; V, volume of distribution. Values reported as range in different populations.

Clearance and Half-Life

Healthy Subjects.

The t½ of nitrazepam ranges from 18 to 31 hours (184,188,189,191,192,194,195,199,218,219), with similar results after single oral or i.v. doses or with long-term treatment for 14 to 24 days (184,220).

Comedicated Epileptic Patients.

The only clinically significant interaction that has been reported for nitrazepam is potentiation of its effect by coadministration of sodium valproate (221) (Table 17.7.). However, induction of the hepatic microsomal enzyme system by rifampin does increase nitrazepam clearance significantly (222), a finding suggesting that, as with other benzodiazepines, nitrazepam pharmacokinetics may be influenced by hepatic enzyme-inducing antiepileptic drugs.

Elderly Patients.

Somewhat increased mean t½ of 38 to 40 hours have been reported in the elderly (199,220).

Other Concurrent Conditions.

The t½ is also prolonged in obesity because of the increased VD (191). The clearance of nitrazepam is unaffected by chronic renal or hepatic disease (199,200).

Relationship between Serum Concentration and Dose and Effect

Long-term daily nitrazepam doses of 170 to 390 µg/kg have been found to lead to plasma concentrations of 40 to 180 ng/mL in children with epilepsy (220). The peak sedative effects of a single oral dose of 5 mg have been seen about 2 hours before peak plasma concentrations have been reached (223). Moreover, a lack of correlation between the residual effects of nitrazepam and plasma levels has been described (205,218,224).

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