Lack of interaction between cimetidine and carbamazepine

Sonne, Jesper; Lühdorf, K.; Larsen, Niels‐Erik; Andreasen, Per Buch

doi:10.1111/j.1600-0404.1983.tb04834.x

Cited by 17 publications

(9 citation statements)

References 16 publications

(4 reference statements)

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“…1983) caused increased plasma concentrations of carbamazepine leading to intoxications. Cimetidine, a well-known inhibitor of drug metabolism, does not seem to have any effect on steady-state plasma concentrations of carbamazepine (Levine et al 1985;Sonne et al 1983).…”

Section: Pharmacokinetic Drug Interactionsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Bertilsson

Tomson

1986

Clinical Pharmacokinetics

262

120

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Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression. Most oral formulations of carbamazepine are well absorbed with high bioavailability. The drug is 75% bound to plasma proteins. The degree of protein binding shows little variation between different subjects, and there is no need to monitor free rather than total plasma concentrations. Carbamazepine is metabolised in the liver by oxidation before excretion in the urine. A major metabolite is carbamazepine-10,11-epoxide which is further metabolised by hydration before excretion. This epoxide-diol pathway is induced during long term treatment with carbamazepine. Co-medication with phenytoin or phenobarbitone further induces this metabolic pathway. Some but not all studies indicate an increased metabolism of carbamazepine during pregnancy. The drug crosses the placenta, and the newborns who are exposed to the drug during fetal life eliminate the drug readily after birth. There seems to be no problem to nurse children during treatment with carbamazepine. Metabolism of carbamazepine is comparable in children and adults. Several studies have tried to establish a relationship between plasma carbamazepine and clinical effect in epilepsy, but very few of these are controlled. The best anticonvulsant effect seems to be obtained at plasma concentrations of 15 to 40 mumol/L and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia. Side effects are more frequent at higher plasma concentrations but are also seen within that range. In some patients, with pronounced fluctuation of plasma concentrations during the dosage interval, side effects may be avoided by more frequent dosing. Carbamazepine-10,11-epoxide is a potent anticonvulsant in animal models. During treatment with carbamazepine the plasma concentrations of this metabolite are usually 10 to 50% of those of the parent drug. It has not been possible to establish the relative contribution of the two compounds to the pharmacological effects. The epoxide has therefore been given to humans with the aim of determining the relative potency of the parent drug and its metabolite. After single oral doses of carbamazepine-10,11-epoxide to healthy subjects, the compound was rapidly absorbed. As a mean of 90% of the given dose was recovered in urine as trans-10,11-dihydroxy-10,11-dihydro-carbamazepine, a complete absorption of unchanged epoxide was shown.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Pharmacokinetic Drug Interactionsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Bertilsson

Tomson

1986

Clinical Pharmacokinetics

262

120

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“…They reported an increase in the AUC and half-life of both carbamazepine and the 10,11-epoxide of between 10 and 20%. Levine et al (1985) and Sonne et al (1983) examined the effect oflong term cimetidine coadministration on carbamazepine pharmacokinetics in long term epileptic patients receiving carbamazepine either alone or in combination with other anticonvulsants. In neither study were the plasma concentrations of carbamzepine altered during cimetidine administration.…”

Section: Carbamazepinementioning

confidence: 99%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

184

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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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“…Cimetidine interacts with many drugs (Somogyi and Muirhead, 1987) causing clinical toxicity in some patients receiving PHT (Kutt, 1989); for chronic treatment, CBZ clearance does not appear to be significantly influenced by cimetidine, and no modification of oral dosages is usually required (Sonne et al, 1983;Levine et al, 1985); VPA clearance can be reduced by cimetidine, but the reduction is small and the clinical significance undefined (Webster et al, 1984). The cimetidine-OCBZ interaction was studied in eight volunteers: cimetidine treatment 800 mg/day for a week did not significantly modify the pharmacokinetics of OCBZ or MHD (Keranen et al, 1992a).…”

Section: Effects Of Other Drugs On Ocbzmentioning

confidence: 99%

Oxcarbazepine: Pharmacokinetic Interactions and Their Clinical Relevance

1994

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Antiepileptic drug (AED) interactions are a common problem during epilepsy treatment. Oxcarbazepine (OCBZ) is a keto homologue of carbamazepine (CBZ) with a completely different metabolic profile. In humans, the keto group is rapidly and quantitatively reduced to form a monohydroxy derivative (MHD), which is the main active agent during OCBZ therapy. MHD is eliminated by renal excretion, glucuronidation and, marginally, by hydroxylation to a diol derivative. This metabolic profile, and in particular the limited involvement of oxidative microsomal enzymes, suggests that OCBZ may have fewer drug interactions compared with traditional AEDs. This possibility has been investigated in experimental studies and, retrospectively, in data obtained from clinical trials. The capacity of OCBZ to induce microsomal enzymes of the P-450 family has mostly been examined by use of antipyrine and CBZ kinetics as markers. The results suggest that OCBZ has little enzyme inducing capacity. In clinical trials in which OCBZ was substituted for CBZ, plasma concentrations of concomitant AEDs were increased, possibly as a consequence of total or partial de-induction. OCBZ interference with other drugs has been evaluated for warfarin, felodipine, and oral contraceptives, three medications strongly influenced by enzyme-inducing AEDs. OCBZ does not modify the anticoagulant effect of warfarin, whereas some reduction in felodipine concentration and a clinically significant reduction of contraceptive drug levels and efficacy were observed. Polytherapy with established AEDs does not significantly modify OCBZ disposition (MHD kinetics); however, available information is not extensive. Finally, the action on OCBZ kinetics of a group of drugs (verapamil, cimetidine, erythromycin, dextropropoxyphene, and viloxazine) known to inhibit the metabolism of some AEDs has been studied.(ABSTRACT TRUNCATED AT 250 WORDS)

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Lack of interaction between cimetidine and carbamazepine

Cited by 17 publications

References 16 publications

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Pharmacokinetic Interactions of Cimetidine 1987

Oxcarbazepine: Pharmacokinetic Interactions and Their Clinical Relevance

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