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.2000 Apr;49(4):313-22.
doi: 10.1046/j.1365-2125.2000.00170.x.

Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes

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Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes

H C Rawden et al. Br J Clin Pharmacol.2000 Apr.

Abstract

Aims: Albendazole (ABZ; methyl 5-propylthio-1H-benzimidazol-2-yl carbamate) is a broad spectrum anthelmintic whose activity resides both in the parent compound and its sulphoxide metabolite (ABS). There are numerous reports of ABZ metabolism in animals but relatively few in humans. We have investigated the sulphoxidation of ABZ in human liver microsomes and recombinant systems.

Methods: The specific enzymes involved in the sulphoxidation of ABZ were determined by a combination of approaches; inhibition with an antiserum directed against cytochrome P450 reductase, the effect of selective chemical inhibitors on ABZ sulphoxidation in human liver microsomes, the capability of expressed CYP and FMO to mediate the formation of ABS, regression analysis of the rate of metabolism of ABZ to ABS in human liver microsomes against selective P450 substrates and regression analysis of the rate of ABS sulphoxidation against CYP expression measured by Western blotting.

Results: Comparison of Vmax values obtained following heat inactivation (3min at 45 degrees C) of flavin monoxygenases (FMO), chemical inhibition of FMO with methimazole and addition of an antiserum directed against cytochrome P450 reductase indicate that FMO and CYP contribute approximately 30% and 70%, respectively, to ABS production in vitro. Comparison of CLint values suggests CYP is a major contributor in vivo. A significant reduction in ABZ sulphoxidation (n = 3) was seen with ketoconazole (CYP3 A4; 32-37%), ritonavir (CYP3 A4: 34-42%), methimazole (FMO: 28-49%) and thioacetamide (FMO; 32-35%). Additive inhibition with ketoconazole and methimazole was 69 +/- 8% (n = 3). ABS production in heat - treated microsomes (3 min at 45 degrees C) correlated significantly with testosterone 6beta-hydroxylation (CYP3A4; P < 0.05) and band intensities on Western blots probed with an antibody selective for 3A4 (P < 0.05). Recombinant human CYP3 A4, CYP1A2 and FMO3 produced ABS in greater quantities than control microsomes, with those expressing CYP3A4 producing threefold more ABS than those expressing CYP1A2. Kinetic studies showed the Km values obtained with both CYP3A4 and FMO3 were similar.

Conclusions: We conclude that the production of ABS in human liver is mediated via both FMO and CYP, principally CYP3A4, with the CYP component being the major contributor.

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Figures

Figure 1
Figure 1
Structures of albendazole (ABZ), albendazolesulpoxide (ABS), albendazole sulphone (ABSO) and other minor metabolites. The asterisk indicates the site where a chiral centreis generated by sulphoxidation
Figure 2
Figure 2
Effects of (a) increasing volumes of cytochrome P450 reductase antiserum (•) and pre-immune serum (○) and (b) increasing concentrations of MET on ABS production in human liver microsomes. Data are mean (s.d) of three livers.
Figure 3
Figure 3
The effects of methimazole (○), heat treatment (▴) and cytochrome P450 reductase antiserum (□) on the kinetics of ABZ metabolism (to ABS) in human liver microsomes. Data arethe mean of three livers. Control values are (•).
Figure 4
Figure 4
The effects of inhibitors of CYP and alternative substrates for FMO on the production of ABS in human liver microsomes. Data are mean (s.d.) of three livers. *P < 0.025; **P < 0.005; ***P < 0.001.
Figure 5
Figure 5
Additive inhibition of ABS production in human liver microsomes by ketoconazole alone (•) and plus methimazole (○). Data are mean (s.d.) of three livers.
Figure 6
Figure 6
Correlation of ABS production with (a) catalytic activity of testosterone 6 hydroxylation (CYP3A4) and (b) density of immunoreactive CYP on SDS-PAGE immunoblotted for CYP3A4.
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