Pharmacokinetic aspects of the interaction between clobazam and cimetidine

Grigoleit, H.-G.; Hajdú, P; Hundt, H. K. L.; Koeppen, D; Malerczyk, V.; Meyer, B. H.; Müller, F. O.; Witte, Peter Uwe

doi:10.1007/bf00544031

Cited by 21 publications

(12 citation statements)

References 16 publications

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“…A single dose of clobazam 30mg was administered to 9 subjects with and without cimetidine 1 g/day for 7 days (Grigoleit et al 1983). Cimetidine significantly increased the AUC (13.88 versus 16.24 mg/L -h) and half-life (22.7 versus 25.1 hours) of clobazam but had no effect on the AUC of desmethylclobazam (5.56 versus 6.19 mg/L-h).…”

Section: Clobazammentioning

confidence: 99%

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Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

183

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The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Clobazammentioning

confidence: 99%

“…Nelson et al (1985) '" 0 -, Clobazam 9 300mg oral 13.9 ± 3.6 16.2 ± 4.4b t (16) Grigoleit et al (1983) 0.…”

Section: Diazepammentioning

confidence: 99%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

183

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“…Further information on CLB PK and PopPK modeling was identified from unpublished reports from the drug sponsor and from references cited in the articles obtained in the literature search. In total, over 100 English‐language articles and abstracts were reviewed; 53 published and 3 unpublished reports were used to compile the information presented here on CLB PK, use in specific patient populations, drug interactions, and PopPK analyses …”

Section: Clobazam Clinical Pharmacokineticsmentioning

confidence: 99%

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Tolbert

Larsen

2018

The Journal of Clinical Pharma

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Clobazam (CLB) is a 1,5‐benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox‐Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single‐ and multiple‐dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N ‐desmethylclobazam. The half‐life of CLB after a single oral dose ranges from 36 to 42 hours; the half‐life of N ‐desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox‐Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.

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“…51 Clobazam and NCLB are both hepatically metabolized by cytochrome P450 2C19 (CYP2C1) 52 while cimetidine has been shown to increase the plasma half-life by approximately 10%. 53 The presumed major mechanism of action for clobazam is similar to that of the 1,4-benzodiazepines, acting on benzodiazepine receptors to potentiate the inhibitory neurotransmitter GABA, on voltage sensitive calcium ion conductance, and on sodium channels. 54,55 Unlike all other benzodiazepines, which have a 1,4 structure, clobazam is the only 1,5-benzodiazepine available.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Clobazam

Collins

2007

Neurotherapeutics

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Pharmacokinetic aspects of the interaction between clobazam and cimetidine

Cited by 21 publications

References 16 publications

Pharmacokinetic Interactions of Cimetidine 1987

Pharmacokinetic Interactions of Cimetidine 1987

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Clobazam

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