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AIMS Chemical inhibitors of cytochrome P450 (CYP) are a useful tool in defining the role of individual CYPs involved in drug metabolism. The aim of the present study was to evaluate the selectivity and rank the order of potency of a range of isoform-selective CYP inhibitors and to compare directly the effects of these inhibitors in human and rat hepatic(More)
1. A number of compounds have been examined for their ability to inhibit tolbutamide hydroxylase activity in human liver microsomes (control value at a substrate concentration of 150 microM being 0.27 +/- 0.12 nmol min-1 mg-1 protein; mean +/- s.d.; n = 7). 2. IC50 (concentration of inhibitor producing 50% inhibition) values were determined for a range of(More)
In this paper we describe the kinetics of formation of 1-methylxanthine (1-MX), 3-methylxanthine (3-MX) and 1,3-dimethyluric acid (1,3-DMU) from theophylline in human liver microsomal incubations and use the selective inhibitor approach to define the role of the individual cytochrome P450s (CYP) in each pathway. A biphasic model fitted the data best for the(More)
Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6(More)
OBJECTIVE The most important hepatic enzyme involved in the metabolism of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy volunteers. In this study we investigated the kinetics of SQV when administered alone and in combination with RIT in HIV-infected(More)
Four antimycotic drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine have been studied for their effect on the metabolism of cyclosporin by human liver microsomes (n = 3) in vitro. Ketoconazole caused marked inhibition of cyclosporin hydroxylase (to metabolites M17 and M1) with IC50 and Ki values of 0.24 +/- 0.01 and(More)
1. 2',3'-Dideoxyinosine (ddI) has potent activity against human immunodeficiency virus (HIV). It is converted within target cells to its active form dideoxyadenosine triphosphate(ddA-TP). 2. In addition to the intracellular formation of ddA-TP, ddI can be broken down to hypoxanthine, by purine nucleoside phosphorylase (PNP) and to uric acid, by xanthine(More)
Patients taking oral contraceptive steroids (OCS) are known to suffer contraceptive failure while taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine. We have studied the single dose kinetics of ethinyloestradiol (EE2); 50 micrograms, and levonorgestrel (Ng); 250 micrograms in groups of women before and 8-12 weeks after starting(More)
Patients taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine together with their oral contraceptive steroid may suffer contraceptive failure because of the enzyme-inducing properties of these anticonvulsants. We have examined, in six women, the effect of sodium valproate, an effective broad spectrum anticonvulsant, on the area under(More)
The effects of sulphaphenazole, cimetidine and primaquine on the disposition of antipyrine and tolbutamide in healthy volunteers have been investigated. The model substrates were administered simultaneously in order more clearly to define any selective effects of the potential inhibitors. Sulphaphenazole produced a significant increase in the half-life of(More)