Co-administration Of Rifampicin Research Articles

Genotyping of the N-acetyltransferase2 Polymorphism in the Prediction of Adverse Drug Reactions to Isoniazid in Japanese Patients

To investigate the association between NAT2 genotypes and the incidence of isoniazid (INH)-induced adverse reactions, in the hope of identifying a pharmacogenetic approach that could be useful in the prediction and prevention of adverse reactions in Japanese patients, we retrospectively studied the genotypes of NAT2 in 102 Japanese patients treated with INH (without rifampicin co-administration). The subjects were classified into three groups according to their genotypes: rapid-type, intermediate-type, and slow-type. The clinical conditions of the patients were followed-up in order to evaluate the development of any adverse drug reactions (ADRs) and correlate them with patient genotypes. Six out of the 102 patients (5.9%) developed various ADRs following INH treatment. These reactions included nausea/vomiting, fever, visual impairment, and peripheral neuritis. We found a statistically significant difference between the incidence of ADRs and NAT2 genotype. The incidence of ADRs was significantly higher in the slow type than in the other two types, as 5 out of the 6 ADR patients were of the slow-type, and the other one was of the intermediate-type, while no patients of the rapid-type developed any ADRs. The results indicated that the genes coding for slow acetylation were associated with the incidence of serious ADRs following INH treatment. Our findings suggest that determination of NAT2 genotype might be clinically useful in the evaluation of patients at high risk of developing ADRs induced by INH.

Time-dependent pharmacokinetic interaction between zidovudine and rifampicin following oral administration at 10.00 and 22.00 hours.

Rifampicin, an antitubercular agent, is a known metabolic inducer. Previous studies have suggested that rifampicin may interfere with the pharmacokinetics of oral zidovudine when the two drugs are co-administered. Circadian variations in the pharmacokinetics of rifampicin have been reported. We report here a circadian influence on the pharmacokinetics of zidovudine in the presence of rifampicin when administered orally in rabbits. Either zidovudine or zidovudine with rifampicin was administered orally at 10.00 or 22.00 h to 12 healthy rabbits in a randomized cross-over study. Serum zidovudine was estimated by HPLC. A significant (p <0.05) lowering of Cmax, (1/2), AUC(0-6h) and MRT was observed following zidovudine and rifampicin co-administration compared to zidovudine alone at 10.00 h. Accordingly clearance increased to a significant extent. However, such an interaction effect was masked following administration at 22.00 h. The time-dependent influence of rifampicin on the pharmacokinetics of zidovudine may be due to time-dependent changes in absorption and elimination of rifampicin, thus modifying its induction effect on the levels of UDP glucuronyl transferase and cytochrome P-450 content in liver which are responsible for metabolism of zidovudine.

Pharmacokinetics of haloperidol: an update.

Haloperidol is commonly used in the therapy of patients with acute and chronic schizophrenia. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase and uridine diphosphoglucose glucuronosyltransferase. The greatest proportion of the intrinsic hepatic clearance of haloperidol is by glucuronidation, followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of CYP-mediated disposition in vitro, CYP3A4 appears to be the major isoform responsible for the metabolism of haloperidol in humans. The intrinsic clearances of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude, suggesting that the same enzyme system is responsible for the 3 reactions. Large variation in the catalytic activity was observed in the CYP-mediated reactions, whereas there appeared to be only small variations in the glucuronidation and carbonyl reduction pathways. Haloperidol is a substrate of CYP3A4 and an inhibitor, as well as a stimulator, of CYP2D6. Reduced haloperidol is also a substrate of CYP3A4 and inhibitor of CYP2D6. Pharmacokinetic interactions occur between haloperidol and various drugs given concomitantly, for example, carbamazepine, phenytoin, phenobarbital, fluoxetine, fluvoxamine, nefazodone, venlafaxine, buspirone, alprazolam, rifampicin (rifampin), quinidine and carteolol. Overall, drug interaction studies have suggested that CYP3A4 is involved in the biotransformation of haloperidol in humans. Interactions of haloperidol with most drugs lead to only small changes in plasma haloperidol concentrations, suggesting that the interactions have little clinical significance. On the other hand, the coadministration of carbamazepine, phenytoin, phenobarbital, rifampicin or quinidine affects the pharmacokinetics of haloperidol to an extent that alterations in clinical consequences would be expected. In vivo pharmacogenetic studies have indicated that the metabolism and disposition of haloperidol may be regulated by genetically determined polymorphic CYP2D6 activity. However, these findings appear to contradict those from studies in vitro with human liver microsomes and from studies of drug interactions in vivo. Interethnic and pharmacogenetic differences in haloperidol metabolism may explain these observations.

Pharmacokinetics of Lamisil® in humans

The pharmacokinetics of terbinafine (Lamisil) have been studied in humans using both unlabelled and radiolabelled drug. Lamisil is well absorbed (> 70%) while maximal plasma concentrations of parent drug are reached within 2 hours following oral administration. Lamisil is extensively distributed to all tissues in the body with a total volume of distribution of approximately 1000 I (Vd). The half-life of elimination (β-phase) of Lamisil in man is approximately 16 hours. Lamisil is not excreted as an unchanged drug but is completely metabolized in the liver; 15 metabolites have been identified. Lamisil does not affect the metabolism of antipyrine, but its own metabolism is modified by the coadministration of either cimetidine or rifampicin.

Interaction of bisoprolol with cimetidine and rifampicin.

In 6 healthy volunteers the pharmacokinetics of bisoprolol under steady-state conditions was investigated over three consecutive phases: over 7 days of 10 mg of bisoprolol once daily per os, 7 days of 10 mg of bisoprolol once daily plus 400 mg of cimetidine t.i.d. and 14 days of 10 mg of bisoprolol and 600 mg of rifampicin once daily with adequate intervals free of medication. After therapy with bisoprolol alone peak plasma levels (Cssmax) of the beta-blocker were 55.5 +/- 6.4 ng/ml (means +/- SEM), area under the plasma level-time curve (AUC tau) was 597 +/- 70 ng/ml.h, total body clearance (CL) 15.8 +/- 1.8 l/h and elimination half-lives (t1/2 beta) 10.1 +/- 1.2 h. Cimetidine did not cause any significant changes in the pharmacokinetics of bisoprolol. Co-administration of rifampicin resulted in a decrease in Cssmax (43.0 +/- 6.9 ng/ml), AUC tau (397 +/- 54 ng/ml X h) and t1/2 beta (6.2 +/- 0.4 h). Accordingly, total body clearance increased to 23.8 +/- 2.5 l/h (p less than 0.05). In conclusion bisoprolol showed a statistically significant but probably clinically not important interaction with the enzyme-inducing drug rifampicin, but not with the enzyme inhibitor cimetidine.