Metabolism of rifabutin in human enterocyte and liver microsomes: Kinetic parameters, identification of enzyme systems, and drug interactions with macrolides and antifungal agents*

Abstract

Biotransformation of rifabutin, an antibiotic used for treatment of tuberculosis in patients infected with the human immunodeficiency virus (HIV), and its interactions with some macrolide and antifungal agents were studied in human intestinal and liver microsomes. Both liver and enterocyte microsomes metabolized rifabutin to 25-O-deacetylrifabutin, 27-O-demethylrifabutin, and 20-, 31-, and 32-hydroxyrifabutin. The same products (except 25-O-deacetylrifabutin) were formed by microsomes from lymphoblastoid cells that contained expressed CYP3A4. The apparent Michaelis-Menten constant (Km); approximately 10 to 12 mumol/L) and maximal velocity (Vmax; approximately 100 pmol/min/mg of protein) values for CYP-mediated metabolism were similar in liver and enterocyte microsomes. Deacetylation of rifabutin (Km approximately 16 to 20 mumol/L and Vmax approximately 50 to 100 pmol/min/mg of protein) was catalyzed by microsomal cholinesterase. Clarithromycin, ketoconazole, and fluconazole inhibited CYP-mediated metabolism of rifabutin in enterocyte microsomes equally or more potently than in liver microsomes but had no effect on cholinesterase activity. Azithromycin did not inhibit in vitro metabolism of rifabutin. This study provides evidence that CYP3A4 and cholinesterase are major enzymes that biotransform rifabutin in humans and that intestinal CYP3A4 contributes significantly to rifabutin presystemic first-pass metabolism and drug interactions with macrolide and antifungal agents.

The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts

“…AFB 1 damage was induced using a microsomal activation system. Microsomes were prepared as described (Koudriakova et al, 1996;Iatsimirskaia et al, 1997), either from dexamethasone-or phenobarbitaltreated male adult Sprague-Dawley rats. In all experiments, except where indicated, microsomes isolated from dexamethasone-treated rats were used.…”

Rifabutin‐based Helicobacter pylori eradication ‘rescue therapy’

“…2,3 Important drug interactions with commonly-used antibiotics can also be speculatedÐfor example, with clarithromycin in combination therapy, because rifabutin induces cytochrome P-450. 4 Finally, since the Italian Ministry of Health and the FDA indications for the use of rifabutin are restricted to prevention or cure of Mycobacterium avium complex disease in HIV-infected patients, the use of this drug outside this indication is questionable.…”

Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

“…In a previous study, concomitant omeprazole increased the average AUC of voriconazole by about 40% (32); however, the magnitude of this increase does not require adjustments in the voriconazole dose when coadministered with omeprazole (17). In contrast, fluconazole inhibits CYP2C19 and CYP3A4 with K i s of 2.1 M and 25.2 M (mean of the values reported in the literature), respectively (4,8,10,31,34), and hence, it is not unexpected that its overall effect on voriconazole levels is greater than that of omeprazole.…”

“…Serial plasma samples for voriconazole pharmacokinetics were collected predosing and at 1,2,3,4,6,8,10,12,16,24,36, and 48 h after dosing on day 4. Plasma samples were assayed for voriconazole by a previously validated method using automated solid-phase extraction, followed by liquid chromatographic tandem mass spectrometric analysis (1).…”

“…The inhibition constant (K i ) of fluconazole for the CYP2C19 enzyme used for simulating drug-drug interaction was 2.1 M (31). The literature reports K i values for fluconazole-mediated CYP3A4 inhibition ranging from 1.9 to 63 M; therefore, a mean value of 25.2 M was used as the input for Simcyp modeling (4,8,10,31,34).…”