Metabolism of Anxiolytics and Hypnotics ... - Springer Link

Cellular and Molecular Neurobiology, Vol. 19, No. 4, 1999

Metabolism of Anxiolytics and Hypnotics : Benzodiazepines, Buspirone, Zoplicone, and Zolpidem1 Guy Chouinard,2,3,6 Karen Lefko-Singh,4 and Eric Teboul5 Received April 15, 1997; accepted August 22, 1997; updated April 12, 1999 SUMMARY 1. The benzodiazepines are among the most frequently prescribed of all drugs and have been used for their anxiolytic, anticonvulsant, and sedative/hypnotic properties. Since absorption rates, volumes of distribution, and elimination rates differ greatly among the benzodiazepine derivatives, each benzodiazepine has a unique plasma concentration curve. Although the time to peak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect. The importance of 움 and 웁 half-lives in the actions of benzodiazepines is discussed. 2. The role of cytochrome P450 isozymes in the metabolism of benzodiazepines and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed. 3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extensive metabolism, with hydroxylation and dealkylation being the major pathways. Pharmacokinetic interactions of buspirone with other coadministered drugs seem to be minimal. 4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, and decarboxylation of zopiclone occur, and zolpidem undergoes oxidation of methyl groups and hydroxylation of a position on the imidazolepyridine ring system. Zopiclone has a chiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug–drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interactions of zolpidem with coadministered drugs; however, it has been reported to affect the Cmax and clearance of chlorpromazepine and to decrease metabolism of the antiviral agent ritonavin. Since CYP3A4 has been reported to play an important role in metabolism of zolpidem, possible interactions with drugs which are substrates and/or inhibitors of that CYP isozyme should be considered. KEY WORDS: benzodiazepines; cytochromes P450; oxidation; reduction; conjugation; drug interactions.

1

Portions of this review were taken from a previous paper (Teboul and Chouinard, 1990) with permission from the authors and the Canadian Psychiatric Association. 2 Psychiatric Research Centre, Louis-H. Lafontaine Hospital, Department of Psychiatry, University of Montreal, Montreal, Quebec H1N 3M5, Canada. 3 Allan Memorial Institute, Department of Psychiatry, McGill University, Montreal, Quebec H3A 1A1, Canada. 4 Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2R7, Canada. 5 Hoˆtel-Dieu de Saint-Je´roˆme, St. Je´roˆme, Quebec J7Z 5T3, Canada. 6 To whom correspondence should be addressed at Psychiatric Research Centre, Louis-H. Lafontaine Hospital, 7401 Hochelaga, Montreal, QC H1N 3M5, Canada. 533 0272-4340/99/0800-0533$16.00/0  1999 Plenum Publishing Corporation

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Chouinard, Lefko-Singh, and Teboul

INTRODUCTION In this review, the metabolism of several drugs which are used primarily as anxiolytics and/or hypnotics is considered. These drugs include benzodiazepines, buspirone, zopiclone, and zolpidem.

BENZODIAZEPINES Since their introduction in 1960, benzodiazepines have rapidly become the drugs of choice in the treatment of anxiety and insomnia (Woods et al., 1992). Benzodiazepines account for two-thirds of prescriptions for psychotropic drugs and are, in fact, among the most widely prescribed drugs of any class (Marks, 1985a; Gelenberg, 1983; Baldessarini, 1985; World Psychiatric Association Report, 1996). Several thousand different benzodiazepines have been synthesized (Hollister, 1985), and there are now approximately 50 types available worldwide for clinical use (Haefeley et al., 1985). Although there are many similarities between various benzodiazepine derivatives, there are also significant differences. These differences should form the basis for a rational choice among the various derivatives to suit the needs of a given clinical situation. In this paper, pharmacokinetic principles applicable to the benzodiazepines are reviewed. Information on the 14 benzodiazepines currently available for clinical use in Canada is provided (Table I). Chemistry Benzodiazepines are named as such because their core structure consists of a benzene ring fused to a seven-membered 1,4 diazepine ring (Fig. 1). Almost all of them also have a 5-aryl substituent ring. They differ from one another in the chemical nature of the substituent groups at positions 1, 2, 3, and 4 (of the diazepine ring), position 7 (of the benzene ring), and position 2⬘ (of the 5-aryl substituent ring). Based on common R-group substituents, five pharmacologic subgroups have been defined: the 2-keto benzodiazepines, the 3-OH benzodiazepines, the 7-nitro benzodiazepines, the triazolo benzodiazepines, and, the imidazo benzodiazepine midazolam. Derivatives in a given subgroup are metabolized in the liver by similar mechanisms and therefore have half-lives within the same ranges (Greenblatt et al., 1983a; Harvey, 1985). However, even benzodiazepines with very similar chemical structures can differ greatly in their potency, rate of absorption, and other important parameters. Pharmacokinetics Appropriate clinical use of benzodiazepines requires an understanding of, and familiarity with, the principles of both pharmacokinetics and pharmacodynamics. Pharmacokinetics has been described as ‘‘what the body does to the drug,’’ and pharmacodynamics as ‘‘what the drug does to the body’’ (McKenzie, 1983). Whereas pharmacokinetics includes processes such as absorption, distribution, localization

2-Keto

2-Keto 3-OH 2-Keto

2-Keto 7-Nitro 3-OH Triazolo 3-OH 2-Keto

7-Nitro 2-Keto Triazolo Imidazo

Benzodiazepine

Chlordiazepoxide

Diazepam

Oxazepam Flurazepamb

Clorazepate Clonazepam Lorazepam

Triazolamb Temazepamb Ketazolam

Nitrazepamb Bromazepam Alprazolam Midazolam 10 3 0.5 2

0.25 30 15

7.5 0.25 1

15 30

5

10

1–5 1–4 1–2 0.3–0.5

1–5 2–3 2–3

0.5–2.5 1–2 1–5

2–4 0.5–1.5

0.5–1.5

1–4

Time to peak plasma levels (hr)c

3–6 0.25–1

15–30

3.75–22.5 0.5–2 0.5–2

10–30

2–10

5–25d

Single dose (mg)

5–10 HS 6–18 0.75–4 im:e 0.07–0.08 mg/kg (up to 5 mg in adults) (iv:e 0.03–0.035 mg/kg) (or 2.0–2.5 mg in adults)

0.125–0.5 HS 15–30 HS

7.5–30 1–10 2–6

30–60 15–30 HS

4–40

15–60

Usual daily dose (mg/day)

Adult dosage

60 10

90 30 10

120

60

100d

Maximal dose (mg/day)

3.75/7.5/30 mg 0.5/2 mg S/L, 0.5/1/2 mg iv: 4 mg/ml (4-ml amps) 0.125/0.25 mg 15/30 mg 15/30 mg

2/5/10 mg iv: 10 mg in 2-ml amps 10/15/30 mg 15–30 mg

po: 5/10 mg po: 1.5/3/6 mg po: 0.25/0.5 mg im: 1 mg/ml (vials of 2.5 & 10 ml) iv: 5 mg/ml (vials of 1, 2, 5, & 10 ml)

po: po: po: im, po: po: po:

po: im, po: po:

po: 5/10/25 mg im, iv: 50 mg/ml (100 mg in 2-ml amps)

Methods of administration and supplied forms

1-Hydroxymethylmidazolam (1–4)

Triazolam (2–6) Temazepam (5–20) Diazepam (14–100) Desmethyldiazepam (30–100) Desmethylketazolam Nitrazepam (20–40) Bromazepam (8–19) Alprazolam (6–20) Midazolam (1–4)

Chlordiazepoxide (7–30) Desmethylchlordiazepoxide (10–30) Desmethyldiazepam (30–100) Demoxepam (30–60) Diazepam (14–100) Desmethyldiazepam (30–100) Oxazepam (5–20) Desalkylflurazepam (40–100) Hydroxyethylflurazepam (2–4) (Flurazepam aldehyde) (1–2) Desmethyldiazepam (30–100) Clonazepam (20–80) Lorazepam (10–20)

Active substances in blood (웁 half-life)

0.29 0.24 0.54 1.54

1.00 0.79

0.64

0.56 0.20 0.79 0.28 0.48

1.00 0.79 0.45

Lipophilicity f

c

b

The information was derived from values from the sources referred to in footnote g. Values chosen represent those with the greatest degree of consensus and/or our own experience. Only approved indication is for HS sedation. Values are for po doses except for midalozam, where the stated value is for an im dose. im Iorazepam and midalozam are well absorbed, whereas im diazepam and chlordiazepoxide are variably and inconsistently absorbed. iv forms of chlodiazepoxide, diazepam, lorazepam, and midazolam all reach peak plasma levels between 15 sec and a few minutes. d im dose is 25–100 mg, with a maximum of 300 mg. e For preanesthetic use only (see CPS for complete dosage information). f Relative to diazepam. g References: Gelenberg, 1983; Baldessarini, 1985; Grenblatt et al., 1982, 1983a, b, 1985; Harvey, 1985; Jochemsen and Breimer, 1984; McEvoy, 1989; CPS, 1989; Salzman, 1980; Shaefer, 1987; Cook, 1986; Kales et al., 1985; Hyman, 1988; Cooper, 1982; Smith and Wesson, 1985; Ochs et al., 1987; Klotz et al., 1980; Rickels, 1985.

a

Chemical class

Approximate dose equivalence

Table I. Information on Benzodiazepines Available in Canadaa

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Fig. 1. The structure of benzodiazepines.

in tissues, biotransformation, and excretion, pharmacodynamics refers to the physiological effects of a drug, including both the therapeutic and adverse effects and the body’s compensatory homeostatic adjustments to the presence of the drug. This review discusses pharmacokinetic aspects, including metabolism, of the benzodiazepines. The influence of different pharmacokinetic variables on benzodiazepine action is initially considered as if pharmacodynamic parameters remain constant while the drug remains in the body. In fact, however, pharmacodynamic tolerance greatly influences the duration of clinical effects. In a pure pharmacokinetic model (Dettli, 1986) two assumptions are made: (1) plasma concentrations are directly proportional to concentrations of the drug at the receptor site throughout the three phases of absorption, distribution, and elimination; and (2) the clinical effect of the drug is directly correlated with drug plasma concentrations above a minimal effective concentration (Cmin). Below this concentration, no clinical effects are produced. Whereas assumption 1 is generally accepted because benzodiazepines are highly lipophilic and readily equilibrate across the blood–brain barrier (Greenblatt et al., 1987), assumption 2 is somewhat more controversial. Clear concentration–effect correlations can, in fact, be demonstrated in certain experimental designs. For example, the minimal effective sedative concentration (Cmin) of flunitrazepam has been determined experimentally as approximately 3 애g/ml (Amrein et al., 1979). The concept of Cmin is used frequently in benzodiazepine pharmacokinetic models (Dettli, 1986; Greenblatt and Shader, 1987; Jochemsen and Breimer, 1984). It is clear, however, that this concept has certain limitations. The minimal effective concentration may vary with the clinical effect being measured and the method used to measure it. In addition, the concentration–effect relationship may be greatly affected by the development of a pharmacodynamic tolerance.

Anxiolytics and Hypnotics

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Single-Dose Pharmacokinetics Figure 2 shows a simulated plasma concentration curve which illustrates a typical time course of benzodiazepine plasma levels after a single-dose. The course follows three phases: the absorption phase, during which plasma levels rise as the drug is absorbed into the circulation; the distribution phase, in which there is usually a steep drop in plasma levels as the drug leaves the circulation to enter peripheral tissues such as fat, skeletal muscle, and liver (Greenblatt et al., 1987); and the elimination phase, which begins with the attainment of distribution equilibrium and during which the drug disappears from all body compartments simultaneously at a rate determined solely by the elimination rate (Greenblatt et al., 1987). Since absorption rates, volumes of distribution, and elimination rates of the benzodiazepine derivatives differ greatly, each derivative has a unique plasma concentration curve. Time to Onset of Clinical Action The time to onset of clinical effect (to) is the time period from ingestion to the point at which Cmin is reached (Fig. 2). Most reviews estimate the time to onset of clinical effect using words such as ‘‘rapid’’ and ‘‘intermediate’’ (Greenblatt et al., 1983b) or using the time to reach peak plasma levels (tppl). Although the time to peak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect; for example, the peak plasma level for clonazepam is reached 1 to 2 hr after ingestion (McEvoy, 1989), but its onset of clinical effect has been quoted as occurring within 20 to 40 min (McEvoy, 1989). The higher the rate of absorption, the more tppl approximates to . The absorption rate of a drug is an important determinant of the time required for the clinical effects to appear. A rapidly absorbed drug such as diazepam or flurazepam will rapidly produce a high peak plasma level. This would correlate with a rapid and intense onset, which may be sleep-inducing or experienced as a ‘‘rush’’(Weiershausen, 1985). A drug which is absorbed at a slower rate, such as

Fig. 2. Computer-simulated benzodiazepine plasma concentration–time curve.

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oxazepam or temazepam, will have a longer latency period before its effect becomes perceptible (to) and will produce a lower peak (Dettli, 1986), which is perceived by the patient as less intense and more gradual (see Fig. 3). Oral Dosing There are several steps between the ingestion of a drug and its onset of action. Once ingested, the formulation is acted upon by the gastric juice, which dissolves it and releases the drug from its vehicle. For some derivatives the gastric juice modifies the chemical structure of the drug at this early stage. (For example, clorazepate is a prodrug modified by acid hydrolysis in the stomach to form desmethyldiazepam, and only the latter compound ever reaches the blood.) In the next step, the drug must be moved from the stomach to the proximal small bowel, where it is absorbed into the bloodstream (Divoll et al., 1982; Greenblatt et al., 1978). It then crosses the blood–brain barrier by passive diffusion to reach its receptors on the neuronal membrane, where it exerts its effects. Since benzodiazepines are all highly lipophilic agents, the last step occurs quite rapidly. Thus, the rate-limiting step in oral dosing is the rate of absorption from the GI tract. Anything that slows gastric emptying (for example, coadministration with anticholinergic medication) will delay the onset of clinical effects. Even the presence of food can delay the absorption somewhat, and tablets are more rapidly absorbed than capsules (McEvoy, 1989). After having reached the proximal small bowel, the rate of absorption is dependent on intrinsic physicochemical properties of the drugs and, to a lesser extent, on the characteristics of the pharmaceutical formulation (for example, particle size) (Greenblatt et al., 1983b). Sublingual Administration Only lorazepam is currently available in a form suitable for sublingual administration. It was developed in the hope that, by bypassing the gut, a more rapid onset

Fig. 3. Computer-simulated plasma concentration/equipotent dose versus time for two benzodiazepines with different absorption rates. Administered at equipotent doses, a rapidly absorbed benzodiazepine (A) will produce a higher and more distinct peak than a slowly absorbed benzodiazepine (B).


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could be achieved similar to that with intramuscular administration. However, Greenblatt et al. (1982) found that the sublingual formulation was absorbed at a rate that did not differ significantly from that of regular oral administration of the standard tablets or even from that of sublingual administration of the standard oral tablets. Intramuscular Administration Four benzodiazepines formulated to be administered intramuscularly are currently available for clinical use in Canada: chlordiazepoxide, diazepam, lorazepam, and midazolam. Chlordiazepoxide may precipitate locally and is poorly and slowly absorbed; diazepam is absorbed in a variable and unpredictable manner (Greenblatt et al., 1983b). The use of these two preparations is rarely justified in light of the much more rapid and reliable absorptions achieved with the intramuscular forms of lorazepam (Salzman, 1980; Shaefer, 1987) and midazolam (Shaefer, 1987). There is little experience with midazolam except for preanaesthetic use. Intramuscular clonazepam is also absorbed rapidly and reliably but is not yet available for clinical use. As the rates of absorption with intramuscular lorazepam, midazolam, and clonazepam are higher than that for oral administration, the peak plasma levels achieved are higher and thus the clinical effect is more intense. Intravenous Administration Intravenous administration bypasses absorption, which is the rate-limiting step for oral, sublingual, and intramuscular administration. The time to clinical onset is determined only by the time it takes for the blood to circulate from the intravenous injection site to the brain and for the drug to diffuse passively across the blood–brain barrier. For all the intravenous forms, this generally takes from 15 sec to 5 min (Greenblatt et al., 1983b; McEvoy, 1989). Within this narrow range, the benzodiazepines which have a greater affinity for lipids, such as midazolam and diazepam, may have relatively higher rates of onset of action than lorazepam, but this is not a consistent finding (Greenblatt et al., 1983b). Duration of Action Volume of Distribution and Rate of Elimination As illustrated in Fig. 2, there is a substantial initial decrease in the plasma concentration after peak plasma levels are reached during the distribution phase, which levels off into the more gradual decline of the elimination phase. Evidently, this complex curve cannot be explained by a single half-life. In fact, there are two half-lives: the 움 half-life, the rate of decline in plasma concentrations due to the process of drug redistribution from the central to the peripheral compartment; and the 웁 half-life, the rate of decline due to the process of drug elimination due to metabolism to inactive conjugated forms and urinary excretion. We therefore speak of ‘‘two-compartment disposition kinetics.’’ When plotted on a semilogarithmic

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graph, the plasma concentration–time curve is found to be equal to the sum of two straight lines (Fig. 4). The 움 phase has a slope 움 and a half-life, t1/2 움, equal to 0.693/움, whereas the 웁 phase similarly has a slope 웁 and a half-life, t1/2 웁, equal to 0.693/웁 (Greenblatt et al., 1987). As described earlier, the minimal effective plasma concentration (Fig. 2) is the level below which plasma concentrations exert no clinical effects. For most benzodiazepines, once distribution equilibrium has been reached (i.e., the drug has redistributed across its volume of distribution), 95% of the drug in the body is in the tissues (i.e., peripheral compartment) (Cook, 1986). The plasma and brain (i.e., central compartment) concentration is usually below Cmin at this point, such that the rate of further decline described by the t1/2 웁 is of no clinical consequence. Thus, the frequent classification of benzodiazepines into long-, intermediate-, and shortacting categories based on their terminal 웁 half-lives is unfounded (Harvey, 1985; Dettli, 1986; Greenblatt et al., 1983b, 1985, 1987; Greenblatt and Shader, 1985, 1987; Sheehan, 1987; Taylor and Tinklenberg, 1987; Colburn and Jack, 1987). A much more valuable index of the duration of action of a benzodiazepine would be provided by the 움 half-lives; however, data on 움 half-lives are not readily available, perhaps because this is not yet well recognized. Figure 5 illustrates the influence of volume of distribution on duration of action. In curve C, a large volume of distribution leads to rapid elimination of the drug from the blood, since it is redistributed into the peripheral compartment. In the hypothetical curve D, all variables are equal to curve C except for a lower affinity for lipids and thus a smaller volume of distribution. This leads to a higher peak plasma level and a slower egress of the drug from the circulation, thereby increasing the duration of action of the drug, teff . Figure 6 illustrates that, all else being equal, slower elimination will have only a minimal effect on the duration of action because the elimination rate generally contributes to only a minor degree to lower plasma levels during the distribution phase. The plasma drug concentration curves E and F (with higher and lower

Fig. 4. Semilogarithmic plasma concentration curve after iv benzodiazepine dose (Dettli, 1986).


Fig. 5. The effect of volume of distribution on duration of action. Curve D has a smaller volume of distribution due to a lower degree of lipophilicity. This leads to a higher peak plasma concentration and a more prolonged distribution phase, causing an increase in the duration of action.

Fig. 6. The effect of elimination rate on duration of action. A slower elimination rate (curve F) causes only a minor prolongation of the duration of action (Teff) because the elimination rate contributes to the downslope of plasma concentration during the distribution phase. In the elimination phase, however, it is mostly responsible for the decline in plasma concentration, but this process usually occurs at concentrations below Cmin and thus has little clinical relevance.

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elimination rates, respectively) diverge to a significant degree only during the elimination phase, when plasma concentrations are usually well below minimal effective blood concentrations. Midazolam (available only in parenteral form for preanaesthetic use) and triazolam represent special cases in which the rates of elimination from the blood are so high that they do, in fact, contribute significantly to the postpeak decrease in plasma concentration and are important pharmacokinetic determinants of the duration of action. Dosage According to the pure pharmacokinetic model presented here, an increase in the dosage may cause a large increase in the duration of action, because the benzodiazepine plasma levels at the end of the distribution phase may be above the Cmin and so the terminal half-life now becomes a determinant of the duration of clinical action (Dettli, 1986; Greenblatt et al., 1987) (Fig. 7). Absorption Rate On the model curve in Fig. 2, the absorption rate is high; thus, the total duration of action is determined mainly by the rate of distribution. However, if the absorption process is prolonged, the pharmacokinetic profile can be substantially altered, as shown in Fig. 3. In curve B (Fig. 3) the drug is still being absorbed at the same time as it is being redistributed (i.e., entering its sites of peripheral storage). Thus the usually rapid downslope caused by the distribution is obscured by the prolonged

Fig. 7. Effect of the dosage on the duration of action. These computer-simulated plasma concentration curves illustrate that when the dosage is increased from low (G) to high (H), the duration of action (Teff) may be markedly prolonged, especially if plasma concentrations during the elimination phase exceed Cmin , such that the elimination rate becomes a determinant of duration of clinical action.


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absorption process, and benzodiazepine plasma levels remain above Cmin for a longer period of time, prolonging the duration of action, teff (Dettli, 1986). Multiple-Dose Pharmacokinetics With multiple-dose therapy, such as nightly administration for the treatment of insomnia or repeated daily administration for the treatment of anxiety, benzodiazepine accumulation may occur. Rapidly eliminated drugs administered far enough apart will not accumulate, whereas slowly eliminated drugs are more likely to accumulate (Abernethy et al., 1986). Both the extent and the rate of accumulation are dependent on the timing of the doses as well as on the 움 and 웁 half-lives (Dettli, 1986). If the interval between doses is shorter than the distribution phase, accumulation should occur much more rapidly, since the drug is administered at a time when the plasma concentration is still relatively high from the previous dose. In the treatment of chronic anxiety, accumulation is desirable, since it can provide steady-state plasma levels in an effective concentration range such that an enduring anxiolytic effect is maintained. This prevents large fluctuations in plasma levels between doses often seen with rapidly eliminated compounds and avoids recurrent cycles of symptoms which can occur as the plasma levels drop below the minimal effective concentration (Weiershausen, 1985). In the treatment of chronic insomnia, however, this model proposes that slowly eliminated benzodiazepines lead to cumulative daytime sedative effects as well as accumulation of other adverse effects, such as impairment of psychomotor and intellectual performance. In fact, the degree of central depression accompanying long-term use of benzodiazepines does not increase in proportion to increasing plasma level (Greenblatt et al., 1983b; Greenblatt and Shader, 1986). This divergence between the response predicted by a purely pharmacokinetic model and the actual clinical effects observed can be explained by the phenomenon of pharmacodynamic tolerance, or adaptation (Greenblatt and Shader, 1986).

METABOLISM AND POSSIBLE METABOLIC INTERACTIONS OF BENZODIAZEPINES WITH COADMINISTERED DRUGS Metabolism of Benzodiazepines To be excreted in the urine, benzodiazepines must first be conjugated in the liver to form pharmacologically inactive, water-soluble glucuronide metabolites (Greenblatt et al., 1983a; Harvey, 1985). The 3-OH benzodiazepines, oxazepam, lorazepam, and temazepam, by virtue of their 3-OH group, can be conjugated directly. The 2-keto benzodiazepines must first be metabolically converted through oxidative reactions into 3-OH derivatives before they can be conjugated. These oxidative reactions yield pharmacologically active intermediates with long half-lives. The triazolo and imidazo benzodiazepines are also transformed into hydroxylated compounds prior to conjugation, but these hydroxylated intermediates, although quite active, are conjugated very rapidly and therefore do not accumulate appreciably (Harvey, 1985; Shaefer, 1987). The 7-nitro benzodiazepines, clonazepam and

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nitrazepam, are metabolized by reduction of the 7-nitro substituents to form inactive amines which are then acetylated before excretion (Harvey, 1985). The processes of oxidation and nitroreduction are mediated by the hepatic cytochrome P450 (CYP) system (Abernethy et al., 1986), which may be impaired in old age and in patients with significant hepatic cirrhosis, causing prolongation of the terminal 웁 half-lives of benzodiazepines which are metabolized by this system. Most known drugs and xenobiotics are metabolized in the body to some extent prior to their excretion. While many enzymes are involved in drug metabolism reactions, the cytochromes P-450 (CYPs) are of particular importance in the oxidative metabolism of endogenous compounds, such as steroids, and of numerous exogenous compounds including drugs, environmental chemicals, and other xenobiotics. In humans, there are at least 14 CYP gene families (1–5, 7, 8, 11, 17, 19, 21, 24, 27, and 51) based on the degree of similarity in the amino acid sequences of the CYP proteins (Nelson et al., 1996). Families 1–3 have been implicated in the metabolism of numerous drugs (Gonzalez, 1992). Some of the gene families contain subfamilies, each designated by a different capital letter and members of which have greater than 55% amino acid sequence similarity and individual CYPs. Within a subfamily, individual CYP isozymes are distinguished by a terminal Arabic number (Nebert et al., 1989, 1991; Nelson et al., 1993). Recent studies have indicated that CYP2C19 is involved in the metabolism of diazepam and that CYP3A3/4 is involved in metabolism of alprazolam, clonazepam, diazepam, midazolam, and triazolam (von Moltke et al., 1993; Andersson et al., 1994; Bertz and Granneman, 1997; Glue and Banfield, 1996; Lane, 1996; Richelson, 1997; Venkatakrishnan et al., 1998). The CYP system is involved in the metabolism of numerous drugs such as ethanol, oral contraceptives, fluoxetine, cimetidine, isoniazid, and propranolol, which, when administered concomitantly with benzodiazepines which use this system, may prolong the 웁 half-lives of these benzodiazepines (Abernethy et al., 1986). However, as shown in Fig. 5, prolonging the 웁 half-life has little or no effect on the duration of action of a benzodiazepine following a single-dose. With chronic use, higher steady-state plasma levels may result. However, as discussed earlier, these plasma levels are poorly correlated with clinical effects, probably because of the complicating influence of pharmacodynamic tolerance. Thus, a slightly increased plasma drug level cannot be simply assumed to have clinical relevance. For example, although a pharmacokinetic interaction between cimetidine and diazepam has been shown repeatedly, no pharmacodynamic consequence of the increased diazepam and metabolite accumulation has been demonstrated (Greenblatt et al., 1984). Thus, although there has been increased awareness of potential pharmacokinetic drug– drug interactions in recent years because of increased knowledge of CYP isozymes and the demonstrated effects of psychiatric drugs such as the selective serotonin reuptake inhibitor (SSRI) antidepressants on those isozymes (Baumann, 1996; Nemeroff et al., 1996; Harvey and Preskorn, 1996a, b; Glue and Bamfield, 1996; Lane, 1996), the clinical importance of altered benzodiazepine clearance from drug interactions or in cirrhotics cannot be assumed but must be demonstrated empirically in controlled clinical studies (Greenblatt and Shader, 1985, 1987). Conjugation is the only metabolic step used by the 3-OH benzodiazepines and is apparently unaffected by old age, liver disease, or drug interactions. Renal


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insufficiency may impair excretion of glucuronide metabolites, causing their accumulation, but this has no demonstrated pharmacologic consequences since these metabolites are inactive (Verbeeck et al., 1976).

Potential Pharmacokinetic Drug–Drug Interactions Involving Benzodiazepines In general, metabolic drug–drug interactions involving coadministered drugs seems to be less of a problem with the benzodiazepines than with some of the other drugs (e.g., antipsychotics and antidepressants) used to treat psychiatric disorders. In this review, we discuss only those interactions from the literature which have indicated a clinical effect resulting from such interactions with benzodiazepines. For a more extensive list of possible drug–drug interactions involving benzodiazepines, readers are referred to several useful books on drug–drug interactions (e.g., Ciraulo et al., 1995; Rizack, 1995; Hansten and Horn, 1997) and recent review articles (Bertz and Grannerman, 1997; Glue and Banfield, 1996; Harvey and Preskorn, 1996a; Lane, 1996; Richelson, 1997). Possible pharmacokinetic interactions of midazolam or triazolam with grapefruit juice should also be considered (Bailey et al., 1998). SSRIs Of the SSRIs, fluvoxamine and norfluoxetine (the N-demethylated metabolite of fluoxetine) are the most potent in vitro inhibitors of CYP 3A3/4; fluoxetine, paroxetine, and sertraline are considerably weaker (Preskorn, 1997; von Moltke et al., 1995, 1996a, b; Richelson, 1997). There have been several in vivo studies investigating the effects of fluoxetine on alprazolam clearance. Coadministration of alprazolam and fluoxetine has been reported to result in an approximately 30% increase in plasma alprazolam concentrations and increased psychomotor effects than when alprazolam is administered alone (Lasher et al., 1991; Sands et al., 1997). Greenblatt et al. (1992) demonstrated that fluoxetine at a dose of 40 mg/day for 10 days resulted in a 25% decrease in the clearance of alprazolam. The administration of fluvoxamine, 100 mg/day for 10 days, resulted in a twofold increase in alprazolam plasma concentrations, with a corresponding 55% decrease in clearance (Fleishaker and Hulst, 1994; Preskorn, 1997). Increased reductions in psychomotor performance and memory occurred secondary to increased plasma alprazolam concentrations, suggesting that when alprazolam and fluvoxamine are coadministered, the dosage of alprazolam should be reduced (Fleishaker and Hulst, 1994). Nefazodone Nefazodone is an inhibitor of CYP 3A3/4 (Barbhaiya et al., 1995; Greene et al., 1995; Richelson, 1997; Greenblatt et al., 1998). Coadministration of nefazadone and triazolam resulted in increased triazolam concentrations and enhanced and sustained pharmacodynamic effects compared with triazolam administration alone (Barbhaiya et al., 1995; Kroboth et al., 1995). Less dramatic but nonetheless clinically significant interactions were also observed when nefazodone was administered with alprazolam (Greene et al., 1995; Kroboth et al., 1995).

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Ketoconazole and Itraconazole Ketoconazole and intraconazole are antimycotics which are very potent inhibitors of CYP 3A3/4; ketoconazole is three orders of magnitude more potent in vitro than fluvoxamine, the most potent SSRI in vitro with regard to CYP 3A3/4 inhibition (von Moltke et al., 1996a; Preskorn, 1997). Coadministration of ketoconazole or itraconazole with triazolam results in a serious pharmacokinetic interaction, with enhanced and sustained pharmacodynamic effects compared to triazolam administration alone (Varhe et al., 1994; von Moltke et al., 1996a). Varhe et al. (1994) recommend that, because of the potentially hazardous consequences of this interaction, triazolam should be avoided in patients using ketoconazole or itraconazole. It has also been demonstrated that the administration of midazolam with either ketoconazole or itraconazole results in pharmacokinetic and pharmacodynamic effects of comparable magnitude (Varhe et al., 1994; Olkkola et al., 1994; von Moltke et al., 1996b). Olkkola et al. (1994) recommend that patients receiving ketoconazole or intraconazole should not be administered midazolam. Macrolide Antibiotics Macrolide antibiotics such as erythromycin, troleandomycin, and josamycin inhibit the CYP 3A3/4 subfamily (Gonzalez, 1992). Erythromycin has been shown to decrease triazolam clearance and increase triazolam elimination half-life (Philips et al., 1986). Troleandomycin significantly increased plasma concentrations of triazolam and prolonged the duration of psychomotor impairment (Warot et al., 1987). Studies have shown that erythromycin interacts with midazolam to increase the plasma area under the curve of oral midazolam fourfold and decrease clearance of intravenously administered midazolam by 54% (Olkkola et al., 1993). Further clinical studies are warranted to assess whether these interactions lead to enhanced and sustained pharmacodynamic effects or toxicity; until then, caution when using triazolobenzodiazepines in patients taking macrolide antibiotics is prudent (Sands et al., 1995). Cimetidine Cimetidine impairs a broad range of hepatic microsomal CYP isozymes. Although there is clear-cut evidence that cimetidine causes decreased clearance of benzodiazepines metabolized by oxidative mechanisms, studies have generally failed to show any corresponding clinical effects of this interaction (Greenblatt et al., 1984; Sands et al., 1995). However, increased cognitive impairment following midazolam administration in persons receiving cimetidine has been demonstrated (Sanders et al., 1993; Sands et al., 1995).

BUSPIRONE Buspirone, an azapirone, is an anxiolytic which does not cause sedation, has minimal effects on psychomotor performance or cognition and does not seem to have abuse potential or dependence liability. The mechanism of its anxiolytic action


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is not yet known, although it is a 5-HT1A receptor agonist and also has a moderate affinity for presynaptic dopamine D2 receptors (Fulton and Brogden, 1997). Buspirone is well absorbed after oral administration (Mayol et al., 1985), but substantial first-pass metabolism reduces the oral bioavailability (Mayol et al., 1985). It is highly bound (⬎95% to plasma protein) (Gammans et al., 1986). Its elimination half-life varies from 2 to 11 hr (Gammans et al., 1985, 1986). Buspirone undergoes extensive metabolism, with at least seven major and five minor metabolites. Hydroxylation and dealkylation represent the major metabolic pathways (Jajoo et al., 1989), and 1-(2-pyrimidinyl)piperazine has anxiolytic activity, albeit apparently weaker than that of the parent drug (Grammans et al., 1986). Pharmacokinetic interactions of buspirone with other coadministered drugs such as the tricyclic antidepressants, benzodiazepines, haloperidol, cimetidine, ranitidine, theophylline, and nonsteroidal anti-inflammatory drugs seem to be minimal (Fulton and Brogden, 1997). The pharmacokinetic properties of buspirone do not appear to be altered in the elderly. Dosage adjustments may be necessary in patients with severe hepatic or renal or renal dysfunction because of decreased elimination of buspirone, although there is considerable interpatient variation (Fulton and Brogden, 1997).

ZOPICLONE AND ZOLPIDEM Zopiclone, a cyclopyrrolone, is a hypnotic agent which is rapidly absorbed, with a bioavailability of approximately 80% (Fernandez et al., 1995). The elimination half-life is approximately 5 hr, and plasma protein binding has been reported to be between 45 and 80% (Fernandez et al., 1995). Zopiclone is extensively metabolized, with the inactive N-demethyl metabolite and the active N-oxide metabolites in urine accounting for 30% of the initial dose. Approximately 50% of the zoplicone is decarboxylated and excreted via the lungs (Fernandez et al., 1995). Zoplicone has a chiral center, and the commercially available product is a racemate. The pharmacokinetics in humans are stereoselective, with higher Cmax , AUC, and terminal half-life values noted with the (⫹)- than with the (⫺)-enantiomer (Fernandez et al., 1993). The concentrations of the (⫹)-enantiomers of N-desmethylzopiclone and zopiclone N-oxide have been reported to be equal to or higher than those of the (⫺)-enantiomers in urine (Fernandez et al., 1993). Lower doses of zopiclone may be required in elderly patients and in patients with hepatic insufficiency. With regard to pharmacokinetic drug–drug interactions, the manufacturer recommends caution when coadministering drugs which are inhibitors of CYP enzymes and mentions cimetidine and erythromycin (Ellis, 1997). Drug–drug interactions have been reported with erythromycin (Aranko et al., 1994), trimipramine, and carbamazepine (Fernandez et al., 1995). Zolpidem, an imidazopyridine, is used as a hypnotic and has only minor anxiolytic, myorelaxant, and anticonvulsant properties and does not produce REM sleep rebound or withdrawal effects. This drug binds selectively to the 웆-1 benzodiazepine receptor subtype associated with the GABAA receptor–chloride ionophone supramolecular complex (benzodiazepines bind to 웆-1, -2, and -3 receptors and zopiclone binds to 웆-1 and -2 receptors) (Priest, 1997). This binding may account for zolpidem’s

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selective effect on sleep at normal therapeutic doses. Zolpidem is absorbed rapidly, and bioavailability is about 70% at usual oral doses. It is bound ⬎90% to plasma protein in healthy volunteers. Zolpidem clearance is high in children and low in elderly patients (for a review of zolpidem pharmacokinetics see Salva and Costa, 1995). This drug is extensively metabolized; three major metabolites have been found in humans, but none appears to be pharmacologically active. The major metabolic routes include oxidation of the methyl groups on the phenyl ring or on the imidazopyridine to alcohols (these metabolites are rapidly converted to carboxylic acids) and hydroxylation of one of the positions in the imidazopyridine ring system (Langtry and Benfield, 1990; Salva and Costa, 1995). Pichard et al. (1995) concluded that the formation of alcohol metabolites of zolpidem is mediated principally by CYP3A4, with a minor contribution from CYP1A2 and CYP2D6. The pharmacokinetics of zolpidem are not affected by coadministration of haloperidol, cimetidine, ranitidine, chlorpromazine, warfarin, digoxine, or flumazenil (review by Salva and Costa, 1995). Zolpidem seems to have no marked effects on pharmacokinetics of imipramine, haloperidol, cimetidine, or rantidine, but effects on the Cmax and elimination half-life of chlorpromazine have been reported (Desiger et al., 1988). Piergres et al. (1996) reported that other than a possible shortening of the action of zolpidem in the presence of fluoxetine, there were no significant pharmacokinetic or pharmacodynamic interactions between zolpidem and fluoxetine. The antiviral agent ritonavir may produce decreased metabolism of zolpidem (Rizack, 1997). Given the reported importance of CYP3A4 in the metabolism of zolpidem, mentioned above, it will be of interest to learn more about possible interactions between inhibitors of this CYP isozyme and zolpidem. BARBITURATES Phenobarbital is no longer used extensively for treatment of anxiety or insomnia but is mentioned briefly here because it is a potent inducer of various CYP isozymes (Guengrich, 1990; Spina et al., 1994). Recent evidence also indicates that CYP2C19 may play a role in the metabolism of phenobarbiatal (Reidenberg et al., 1995). CONCLUSION In summary, the drugs currently used extensively as anxiolytics and hypnotics undergo considerable metabolism. Some cases of pharmacokinetic interactions of these drugs with other potentially coadministered drugs have been reported, and such interactions should be considered as knowledge accumulates about the individual isozymes (e.g., CYP isozymes) involved in metabolism of anxiolytic and hypnotic drugs. REFERENCES Abernethy, D. R., Greenblatt, D. J., and Shader, R. I. (1986). Benzodiazepine hypnotic metabolism: Drug interactions and clinical implications. Acta Psychiatr. Scand. 74 (Suppl. 332):32–38.


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