Steady-state plasma desmethyldiazepam during long-term clorazepate use

Steady-state plasma desmethyldiazepam during long-term

clorazepate use: Effect of antacids The effect of antacid on steady-state plasma desmethyldiazepam (DMDZ) concentrations during

long-term treatment with clorazepate dipotassium (CZP) was evaluated in 10 subjects. Each took 7.5 mg CZP nightly for 30 consecutive nights divided into three 10-day treatments given in random sequence as follows: (I) 7.5 mg CZP nightly with no antacid, (2) CZP nightly with 30 ml Maalox, and (3) CZP nightly with Maalox with an additional 30 ml Maalox three times daily. The overall mean steady-state DMDZ plasma level, measured during the last 3 days of each treatment condition, was 175 nglml. Within-day means ranged from 159 to 202 nglml and were not influenced by treatment condition, time, or trial sequence. DMDZ washout after termination of the 30-day trial was slow, proceeding with a half-life of 75 hr (range, 63 to 109 hr). Thus, Maalox does not alter steady-state DMDZ levels during long-term CZP therapy.

Richard I. Shader, M.D., Domenic A. Ciraulo, M.D., David J. Greenblatt, M.D., and Jerold S. Harmatz, B.A. Boston, Mass. The Department of Psychiatry and Division of Clinical Pharmacology, Tufts University School of Medicine and New England Medical Center Hospital

Clorazepate dipotassium (CZP) is a 1,4benzodiazepine derivative used extensively in clinical practice for anxiety .'3 CZP is rapidly and essentially completely transformed to desmethyldiazepam (DMDZ) before reaching the systemic circulation and as such serves as a prodrug for active DMDZ.7 The transformation of CZP to DMDZ by hydrolysis and decarboxylation in vitro is strongly dependent on pH.1° In acidic aqueous media like that normally encountered in the contents of the human stomSupported in part by grant MH-34223 from the United States Public Health Service. Received for publication Sept. 3, 1981. Accepted for publication Oct. 19, 1981. Reprint requests to: Richard I. Shader, M.D., Department of Psychiatry, Box 1007, New England Medical Center Hospital, 171 Harrison Ave., Boston, MA 02111.

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ach, the transformation occurs almost immediately. On the other hand, at neutral pH conversion of clorazepate to DMDZ is exceedingly slow, possibly approaching gastrointestinal transit time. These in vitro observations suggested that absorption of DMDZ from CZP may be impaired due to reduced gastric acidity (elevated gastric pH) attributable to disease or to co-administration of other drugs such as antacids. 12 Results of clinical kinetic studies are conflicting," 4, 8, 11 but all reported studies have assessed DMDZ plasma concentrations after single doses of CZP; we evaluated steady-state plasma DMDZ concentrations in subjects on long-term CZP therapy, a more clinically relevant situation, and the effect of concurrent antacid therapy on these plasma levels

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Effect of antacids on desmethyldiazepam during clorazepate use

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Methods

Our subjects were six men and four women who were 23 to 34 yr old. All were healthy, active adults showing no evidence of medical disease. Two of the women were taking oral contraceptives, but otherwise subjects were taking no medications on a regular basis. All subjects took a single oral 7.5-mg dose of CZP (Tranxene) nightly for 30 consecutive nights. The 30-day treatment period was divided into three consecutive 10-day trials, during which subjects also took either no antacid, low-dose antacid, or high-dose antacid as follows: (1) 7.5 mg CZP in the evening (approximately 10 P.m.) with 100 to 200 ml tap water. No antacids were taken at any time. (2) 7.5 mg CZP in the evening with 30 ml magnesium aluminum hydroxide mixture (Maalox). No antacid was taken at any other time during the day. (3) 7.5 mg clorazepate in the evening together with 30 ml Maalox as described above. Subjects also took 30 ml Maalox three times daily before meals. All subjects were exposed to all three treatment conditions, with the sequence of exposure randomized among participants. Subjects abstained from alcohol throughout the study.

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No restrictions were placed on timing or content of meals. Venous blood samples were drawn into heparinized tubes before the night's dose of CZP on the final three nights (8, 9, and 10) of each treatment condition, presumed to represent steady state. Plasma samples were also drawn every 2 to 3 days during the 15-day washout period after CZP was stopped. Whole blood samples were centrifuged, and the plasma was frozen until the time of DMDZ assay by electron-capture gas-liquid chromatography.5. 6 Differences between treatment modes in steady-state plasma DMDZ concentrations were assessed by analysis of variance. The apparent half-life (t1/2) of drug washout after termination of treatment was determined by log-linear re-

gression analysis. Results

The overall mean steady-state plasma DMDZ concentration of 175 ng/ml varied widely within and among individuals over time. Within-day mean values ranged from 159 to 202 ng/ml (Fig. 1). Differences in steady-state concentrations attributable to treatment condition did not approach significance (Fig. 1), nor were steady-

182 Shader et al.

Clin. Pharmacol. Ther. February 1982

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state levels related to time or trial sequence. Disappearance of DMDZ from plasma after the study was slow (Fig. 2). Mean apparent t1/2 of drug washout was 75 hr (range, 63 to 109 hr).

Discussion

Single-dose studies of DMDZ plasma levels after oral CZP indicate reduced absorption of the former if gastric pH is elevated by sodium bicarbonate' or after a single therapeutic dose of Maalox." In the latter study, antacid also reduced the intensity of clinical sedative effects attributable to a single dose of CZP. The results of these two studies are consistent with the physicochemical properties of CZP; its conversion to DMDZ is strongly dependent on pH."' " In another study antacid coadministration tended to reduce total absorption of DMDZ from CZP, but the reported effect was not supported statistically.' Ochs et al.' reported that plasma DMDZ concentrations after CZP in Billroth gastrectomy patients with impaired or absent gastric acid se-

cretion did not differ from those in age-matched controls without gastrointestinal disease. In our study, steady-state plasma DMDZ concentrations during the clinically relevant situation of long-term CZP therapy were not influenced by low- or high-dose antacid regimens. These findings and other reports' suggest that in vivo formation of DMDZ from CZP is more complex than predicted in vitro and appears to depend on more than gastric acidity alone. As expected from single-dose studies,2' 14 disappearance of DMDZ from plasma after termination of CZP was slow. Washout 0/2 averaged approximately 3 days. Thus, DMDZ cumulation during long-term therapy with either of its two precursor drugs, CZP or prazepam, will be slow and extensive. This probably accounts for clinical anxiolytic efficacy with once-daily dosing .3' 9 The slow decline in plasma levels after abrupt drug discontinuation may have the effect of delaying or minimizing symptoms attributable to drug discontinuation.

Volume 31 Number 2

Effect of antacids on desmethyldiazepam during clorazepate use

We are grateful for the assistance of Ann Locniskar and R. James Stratton.

References Abruzzo CW, Macasieb T, Weinfeld R, Rider JA, Kaplan SA: Changes in the oral absorption characteristics in man of dipotassium chlorazepate at normal and elevated gastric pH. J Pharmacokinet Biopharm 5:377-390, 1977. Allen MD, Greenblatt DJ, Harmatz JS, Shader RI: Desmethyldiazepam kinetics in the elderly after oral prazepam. CLIN PHARMACOL THER 28:196-202, 1980. Burrows GD, Dumovic P, Smith JA, Norman T, Maguire K: A controlled comparative trial of clorazepate (Tranxene) and diazepam (Valium) for anxiety. Med J Aust 2:525-528, 1977. Chun AHC, Carrigan PJ, Hoffman DJ, Kershner RP, Stuart JD: Effect of antacids on absorption of clorazepate. CLIN PHARMACOL THER 22: 329-335, 1977. Greenblatt DJ: Determination of desmethyldiazepam in plasma by electron-capture GLC: application to pharmacokinetic studies of clorazepate. J Pharm Sci 67:427-429, 1978. Greenblatt DJ, Ochs HR, Lloyd BL: Entry of diazepam and its major metabolite into cerebrospinal fluid. Psychopharmacology 70:89-93, 1980. Greenblatt DJ, Shader RI, Divoll M, Harmatz JS: Benzodiazepines: A summary of pharmaco-

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kinetic properties. Br J Clin Pharmacol 11: 1 IS16S, 1981. Magnus RV, Dean BC, Curry SH: Clorazepate: double blind crossover comparison of a single nightly dose with diazepam thrice daily in anxiety. Dis Nerv System 38:819-821, 1977. Ochs HR, Greenblatt DJ, Allen MD, Harmatz JS, Shader RI, Bodem G: Effect of age and Billroth gastrectomy on absorption of desmethyldiazepam from clorazepate. CLIN PHARMACOL THER 26:449-456, 1979. Raihle JA, Papendick VE: Clorazepate dipotasslum, in Florey R, editor: Analytical profiles of drug substances. New York, 1975, Academic Press, Inc., vol. IV, pp. 92-112. Shader RI, Georgotas A, Greenblatt DJ, Harmatz JS, Allen MD: Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminum hydroxide. CLIN PHARMACOL THER 24:308-315, 1978. Shader RI, Greenblatt DJ: Clinical implications of benzodiazepine pharmacokinetics. Am J Psychiatry 134:652-656, 1977. Shader RI, Greenblatt DJ: The use of benzodiazepines in clinical practice. Br J Clin Pharmacol 11:5S-9S, 1981. Shader RI, Greenblatt DJ, Ciraulo DA, Divoll M, Harmatz JS, Georgotas A: Effect of age and sex on disposition of desmethyldiazepam formed from its precursor clorazepate. Psychopharmacology 75: 193-197, 1981.