Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminum hydroxide Ten healthy volunteers ingested single 15-mg doses ofclorazepate dipotassium (CZP) with 60 ml of water, or with 60 ml of magnesium aluminum hydroxide (Maalox) , on two occasions in a randomized, two-way crossover study. Plasma concentrations of desmethyldiazepam (DMDZ) were determined in multiple sampies drawn during 48 hr after each dose. Mean kinetic variables for DMDZ in CZP-water and CZP-magnesium aluminum hydroxide treatment conditions, respectively, were: peak measured concentration, 273 and 188 ng/ml (p < 0.001); time of peak concentration, 1.8 and 2.8 hr after dose (p < 0.01); apparent absorption half-life, 14.8 and 30.7 min (p < 0.02); area under the 48-hr plasma concentration curve, 6,028 and 5,433 ng/ml X hr (p < 0.02). Self-rated sensations offeeling "spacey," "thinking slowed down," and of generalized sedation, were reported with both treatment conditions, but these subjective effects occurred earlier and were more profound when CZP was taken with water as opposed to magnesium aluminum hydroxide. Thus administration of single doses of CZP with usual doses of a commonly prescribed antacid reduces the rate and extent of appearance in blood of DMDZ (the compound responsible for clinical activity) and attenuates self-rated clinical effects.

Richard I. Shader, M.D., Anastasios Georgotas, M.D., David J. Greenblatt, M.D., Jerold S. Harmatz, and Marcia Divoll Allen, R.N. Boston, Mass. The Psychopharmacology Research Laboratory, Massachusetts Mental Health Center; and the Clinical Pharmacology Unit, Massachusetts General Hospital.

Understanding potential drug interactions involving benzodiazepine derivatives and nonabsorbable antacids is c1inically important. Anxious individuals receiving benzodiazepines comSupported in part by Grant MH-12279 from the United States Public Health Service, and by Grant 77-611 from the Foundations' Fund for Research in Psychiatry. Presented in part at the Seventy-ninth Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Atlanta, Ga., March 31, 1978. Received for publication May 13, 1978. Accepted for publication May 31, 1978. Reprint requests to: Dr. Richard 1. Shooer, Psychopharmacology Research Laboratory, Massachusetts Mental Health Center, 74 Fenwood Rooo, Boston, MA 02115.

308

monly experience functional gastrointestinaI symptoms for which they also take antacids. 9 Conversely, patients with peptic u1cer disease, esophagitis, and hiatus hernia are often prescribed antianxiety agents by clinicians who feel that anxiety may playa role in exacerbating the disease. 9 Use of oral benzodiazepines as preoperative medication, concurrent with antacids to reduce the consequences of aspiration, also is becoming increasingly common. 3 Clorazepate (CZP) dipotassium (Tranxene) is a 1,4-benzodiazepine derivative extensively used as an antianxiety agent. 10 Clorazepate is a prodrug or precursor of desmethyldiazepam

0009-9236/78/0324-0308$00.80/0 © 1978 The C. V. Mosby Co.

Volume 24 Number 3

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Table I. Effect of magnesium aluminum hydroxide coadministration on absorption of desmethyldiazepam from clorazepate Mean (± SE) values Kinetic variables for desmethyldiazepam

Clorazepate with water

Clorazepate with magnesium aluminum hydroxide

Value of Student' s paired t

Level of signijicance (two-tailed test)

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273.3 (±21.9) 1.8 (±0.7) 0.25 (±0.08)

188.0 (±17.7) 2.8 (±0.6) 0.28 (±0.06)

5.26

P < 0.001

3.80

p < 0.01

0.40

NS

14.8 (±3.8) 6,028 (±436)

30.7 (±3.1) 5,433 (±455)

2.95

P < 0.02

3.20

P < 0.02

(DMDZ), forrned by hydrolysis and decarboxylation in the stornach. 7 DMDZ is then absorbed into the systemic circulation and probably accounts for most if not all of the clinical activity of clorazepate. The transformation of CZP to DMDZ is strongly dependent on pH. 16 , 18 At low pH values norrnally found in the stornach, hydrolysis is very rapid, being completed within minutes. However at higher pH values, as could occur in patients with diseases or drug therapy that impair acid secretion, the hydrolysis half-life (t%) is greatly prolonged. At pH values approaching neutral, gastric emptying into the alkali ne duodenum may occur before appreciable hydrolysis takes place. Since intact CZP appears to be absorbed poody due to its polarity, 1 gastric acidity could be a crucial factor in the activation and hence the subsequent clinical activity of CZP. Inasmuch as previous studies of this important clinical question have yielded confticting results, we assessed the interaction of CZP with magnesium aluminum hydroxide (Maalox), a commonly used antacid preparation. Methods

Subjects and procedure. The subjects were 5 males and 5 females, aged 23 to 70 yr. They had no evidence of medical or psychiatric disease and no history of chronic drug use. Subjects ingested a single 15-mg capsule of

CZP in the fasting state on two occasions with at least two weeks elapsing between trials. On one occasion, CZP was taken concurrently with 30 ml of magnesium aluminum hydroxide followed by a second 3D-mI magnesium aluminum hydroxide dose one hour later. On the other trial, CZP was taken together with 30 ml of water, followed by another 30 ml of water one ho ur later. The trial sequence was randomized. Subjects took no food or liquid for 3 hr after dosage. Venous blood sampIes were drawn into heparinized tubes from an indwelling Butterfly cannula, or by separate venipuncture, prior to and at the following times after CZP dosage: 0.25,0.5,0.75,1.0,1.5,2.0,2.5,3,4,6,8, 12, 24, 36, and 48 hr. Plasma was separated and frozen until the time of assay. Two batteries of self-rated 100-mm line scales were used to assess subjective perceptions of mood and psychological functioning during the first 6 hr after each dose. The first visual analogue scale (V AS) has been described in detail elsewhere. l l The second scale (SDS) focused on the sedation-drowsiness dimension and consisted of twelve items utilizing the following words: drowsy, slowed down, sleepy, sedated, tired, worn out, listless, fatigued, exhausted, sluggish, weary, and bushed. The SDS enlarges upon the fatigue subscale of the Profile of Mood States (POMS),14 demonstrated

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to be sensitive to sedating effeets of benzodiazepines. 19 Both batteries of seales were eompleted priorto drug dosage, and at 1.0,2.5, 4, and 6 hr after dosage. Subjeets did not see prior ratings. Analysis of data . Kinetics. DMDZ eoneentrations in all sampIes were determined by eleetron-eapture gasliquid ehromatography. 7 The rate of DMDZ appearanee in plasma was assessed using the peak measured plasma eoneentration, the time of peak eoneentration, and the apparent first-order half-life absorption or appearanee in blood (tlha) determined from iterative least-square regression analysis. 8 The relative eompleteness of DMDZ absorption was assessed from the area under the 48-hr plasma eoneentration eurve, determined using the trapezoidal rule: 13 Differenees between treatment eonditions in kinetie variables and in clinieal ratings were analyzed using paired t tests. C linical effects. The 13 items on the VAS were analyzed separately. Raw scores were normalized by are-sin transformation prior to analysis. Although a single "alert-drowsy" vi-

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Fig. 3. Plasma desmethyldiazepam (DMDZ) concentrations during 48 hr after ingestion of 15 mg of c!orazepate with water or with magnesium aluminum hydroxide. Each point is the mean (± SE) far all subjects at the corresponding time. sual analog scale has been shown to be sensitive to sedative drug effects, 4 we judged that subjects may use different words to express the sensation of "sedation. " Accordingly, the 12 items on the SDS were combined into a single mean score, which was then normalized by arc-sin transformation prior to further analysis. Resu1ts

Rate of absorption. Peak plasma DMDZ concentrations were significantly lower and reached later after CZP dosage when the drug was given with the antacid than with water (Table I; Fig. 1). tV2a was also significantly longer in the antacid treatment condition (Table I, Fig. 2). However, the lag time before the start of first-order absorption did not differ significantly between the two treatment conditions. Thus administration of CZP with magnesium aluminum hydroxide reduces the rate of appearance of DMDZ in blood, although it does not delay the start of absorption. Completeness of absorption. The area under the 48-hr plasma DMDZ concentration curve was significantly reduced by coadministration of antacid (Table I). Plasma DMDZ concentrations at all points in time between 0.5 and 24 hr after dosage were significantly lower in the

magnesium aluminum hydroxide treatment condition (Fig. 3). At 0.5,36, and 48 hr, differences were not statistically significant. Fig. 4 shows plasma concentration curves, together with computer-determined pharmacokinetic functions, for 3 representative subjects. Clinical effects. As in our previous chlordiazepoxide study, 11 the two drug-sensitive items on the V AS were "normal-spacey" and "thinking slowed down-thinking speeded up." Self-ratings of "spaciness" increased with both treatments, but changes were greater and occurred earlier in the CZP-water condition (Fig. 5). Increments in self-rated "spaciness" were greater (paired t = 2.76, P < 0.025) at 1.0 hr after CZP when the drug was taken with water. Likewise, changes in self-ratings of thinking speed in the direction of "thinking slowed down" occurred sooner after drug dosage in the CZP-water condition. It is of interest that selfratings of thinking speed in the CZP-water condition recovered to pre-treatment levels or higher by 6 hr after CZP, whereas "spaciness" did not (Fig. 5). The SDS had a high degree of internal consistency (Cronbach's standardized alpha = 0.99). Self-rated sedation increased with both treatments, but was more profound when CZP was

312

Shader et al.

Clin. Pharmacol. Ther. September /978

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Valurne 24 Number 3

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given with water. Increments in sedation were greater (paired t = 2.34, P < 0.05) at 4 hr after CZP-water dosage. At 2.5 hr after CZP, when increments in sedation were maximal in both treatment conditions, self-rated sedation increments correlated with DMDZ plasma level (r = 0.47, p < 0.025). Discussion

The present study demonstrates that the benzodiazepine antianxiety drug clorazepate taken with clinically relevant doses of a commonly used antacid preparation significantly reduces the rate and extent of appearance in blood of desmethyldiazepam, the transformation product that accounts for the clinical activity of clorazepate. The findings are consistent with in vitro studies showing that the rate of CZP conversion to DMDZ depends on the presence of strong acid. 16o 18 In clinical studies, Abruzzo and associates 2 have shown significant reduction in DMDZ absorption from CZP by sodium bicarbonate. Sokol and associates 20 reported impaired absorption of DMDZ from CZP in patients who had undergone sufficient abdominal radiation therapy to reduce or eliminate gastric acid secretion. Our findings could represent a nonspecific effect of antacid coadministration on benzodiazepine absorption. This seems unlikely, however, since the interaction is different from that observed in studies of other benzodiazepines. Administration of magnesium aluminum hydroxide with chlordiazepoxide reduced the rate of drug absorption but had no influence on the completeness of absorption. 12 In a study of the interaction of diazepam with magnesium trisilicate plus aluminum hydroxide (Gelusil), or with magnesium aluminum hydroxide (Maalox), neither antacid had a significant influence on either the rate or completeness of diazepam absorption. * In a similar study of CZP-magnesium aluminum hydroxide interaction, Chun and associates 5 concluded that magnesium aluminum hydroxide did not significantly influence absorption of DMDZ from CZP. However, close examination of their data suggests that this conclusion could be questioned since the number of *Greenblatt. D. J.: Unpublished data.

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