Cimetidine Impairs Elimination of Chlordiazepoxide (Librium) in Man

Desmond, Paul; Patwardhan, Rashmi; Schenker, Steven; Speeg, Kermit V

doi:10.7326/0003-4819-93-2-266

Cited by 169 publications

(29 citation statements)

References 14 publications

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“…Studies in both man and experimental animals have demonstrated that it is also a potent inhibitor of the hepatic metabolism of a variety of other drugs, including antipyrine (Serlin et al, 1979; Klotz & Reimann, 1980;Roberts et al, 1981), aminopyrine (Pelkonen & Puurunen, 1980), chlordiazepoxide (Desmond et al, 1980), diazepam (Klotz & Reiman, 1980), propranolol (Feely et al, 1981), and warfarin (Serlin et al, 1979). The metabolism of both caffeine (Broughton & Rogers, 1981) and theophylline (Roberts et al, 1981;Jackson et al, 1981;Reitberg et al, 1981) is also inhibited.…”

Section: Introductionmentioning

confidence: 99%

Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.

Vestal¹,

Thummel²,

Musser³

et al. 1983

Brit J Clinical Pharma

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1 The effect of concurrent cimetidine administration on the disposition of theophylline was investigated in eight male patients (56‐78 years) with chronic obstructive pulmonary disease (COPD). 2 The patients, who were taking oral theophylline preparations chronically (384‐1020 mg/day), received a [15N], [13C]‐labelled analogue of theophylline (10 mg i.v.) before and during cimetidine treatment (1200 mg/day p.o.). 3 During cimetidine treatment trough levels of theophylline increased 34% (6.4 +/‐ 0.8 to 8.6 +/‐ 1.0 micrograms/ml, P less than 0.05), half‐life increased 48% (6.5 +/‐ 0.6 to 9.6 +/‐ 0.8 h, P less than 0.001), and total plasma clearance decreased 33% (3.88 +/‐ 0.46 to 2.59 +/‐ 0.33 l/h, P less than 0.001), without a significant change in volume of distribution or protein binding. 4 The effect of cimetidine on plasma levels of theophylline was maximal within 72 h. Levels returned to control values within 48 h after its discontinuation. 5 Although there was no correlation with mean plasma concentrations of cimetidine, the change in clearance of theophylline correlated with initial clearance values (r = 0.72). 6 Cimetidine reduced the plasma clearance of theophylline in patients with COPD to an extent similar to that reported in healthy volunteers.

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Section: Introductionmentioning

confidence: 99%

Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.

Vestal¹,

Thummel²,

Musser³

et al. 1983

Brit J Clinical Pharma

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“…The list of drugs so effected includes the sedatives chlordiazepoxide (Desmond et al, 1980b) and diazepam (Klotz et al, 1979) the oral anticoagulant warfarin (Serlin et al, 1979) the methylxanthines caffeine (Desmond et al, 1980a) and theophylline, (Campbell et al, 1981;Jackson et al, 1981) as well as the hepatic-clearance indicator drugs, antipyrine (Klotz et al, 1979) and aminopyrine (Desmond et al, 1980a). Furthermore, Pelkonen & Puurunen (1980) found that CMT pretreatment in rats caused significant prolongation of hexobarbital sleep and inhibition of aminopyrine N-demethylation without altering benzo(a)pyrene hydroxylation.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, CMT has been shown to depress the clearance of a number of microsomally metabolized drugs in rodents (Desmond et al, 1980a;Pelkonen & Puurunen, 1980) and in man (Desmond et al, 1980b;Klotz et al, 1979;Serlin et al, 1979;Jackson et al, 1981).…”

Section: )mentioning

confidence: 99%

Cimetidine enhancement of cyclophosphamide antitumour activity

Dorr¹,

Alberts²

1982

Br J Cancer

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Summary.-Male DBA2 mice were given 106 P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100mg/kg injection 30 min before cyclophosphamide (CTX). CMT significantly prolonged the survival of groups of mice receiving 50, 100 and 200 mg/kg of CTX 3 days after tumour inoculation.Median survival increased by 5-5 days (P <0-05), 10 days (P <0.05) and 13 days (P < 0.05) respectively. The addition of CMT had the effect of roughly doubling the CTX dose, without increasing the lethality. CMT produced the only long-term survival seen in the study (1-2/10) CMT alone had no apparent antitumour activity. CMT significantly prolonged mean pentobarbital sleep to 28-6-60 min vs only 10 min for phenobarbital treated mice. Both CMT regimens increased the plasma concentration time products for CTX-induced metabolites (NBP) by about 1-3 fold (in contrast to a 33% reduction with phenobarbital). On average the single-dose CMT regimen produced the greatest effect on survival, on pentobarbital sleep duration and on total NBP reactive species. Probable mechanisms for the CMT-CTX interaction include competitive microsomal enzyme inhibition and/or acutely depressed hepatic blood flow. Caution should be used in combining CMT with full doses of CTX and any other highly metabolized antineoplastic agents in man.

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“…It has been shown to inhibit metabolism of the 1,4-benzodiazepines diazepam, desmethyldiazepam, chlordiazepoxide and midazolam (Klotz & Reimann, 1980a,b;Desmond et al, 1980;Klotz et al, 1985). However, it does not interfere with the metabolism of oxazepam or lorazepam which are biotransformed via the glucuronidation pathway .…”

Section: Introductionmentioning

confidence: 99%

The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N‐desmethylclobazam.

Pullar¹,

Edwards²,

Haigh³

et al. 1987

Brit J Clinical Pharma

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1 The effect of cimetidine on the single dose pharmacokinetics of orally administered clobazam and N-desmethylclobazam (NDMC) was studied in volunteers. 2 Cimetidine inhibited the elimination of both clobazam and NDMC and inhibited the rate of formation of NDMC from clobazam. 3 The increase in the AUC for NDMC generated from clobazam was relatively greater than that for clobazam itself. This suggests that NDMC elimination is inhibited to a relatively greater extent than clobazam elimination. 4 The increase in AUC for NDMC generated from clobazam was also relatively greater than that for NDMC administered orally. This would suggest that cimetidine either increases the bioavailability of clobazam or reduces that of NDMC. 5 The increase in the AUC for NDMC and for clobazam in some individuals was of a magnitude which is likely to be clinically significant.

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Cimetidine Impairs Elimination of Chlordiazepoxide (Librium) in Man

Cited by 169 publications

References 14 publications

Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.

Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.

Cimetidine enhancement of cyclophosphamide antitumour activity

The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N‐desmethylclobazam.

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