Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Sampol, Emmanuelle; Lacarelle, Bruno; Rajaonarison, J F; Catalin, J; Durand, Alain

doi:10.1111/j.1365-2125.1995.tb04540.x

Cited by 23 publications

(18 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its IC 50 value (39 mM) closely agreed with the K i value of 0.08 mM 21) for the glucuronidation of the antiviral drug, zidovudine, catalyzed by human hepatic microsomes. Grosso et al reported that ketoconazole is substituted with estrogen bound to sex steroid binding globulin present in the circulat- 1848 Vol.…”

Section: Discussionsupporting

confidence: 66%

Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Satoh¹,

Tomikawa

Takanashi

et al. 2004

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Although the drug-induced side effect of gynecomastia is, in many cases, considered to be a result of drug-estrogen interaction mediated by cytochrome P450 (CYP), the prediction of this side effect for inclusion in package inserts is difficult. This is because in addition to the phase I reaction, the effects of the drug on the entire enzyme system involved in the estrogen pool must be taken into consideration.Thus far, we have attempted to construct a system for predicting drug-induced gynecomastia by not only focusing on the phase I reaction, but also extending the sites of interaction to include estrogen production and regeneration systems. By confirming drug inhibition in those systems, we intend to develop a model unit reaction system for the determination of the percentage inhibition under identical conditions, and to determine its potential for clinical application.2-4) The results obtained are discussed below.The main route of metabolism of estradiol (E2) in humans is the phase I reaction of 2-hydroxylation, and although there are a lot of human hepatic CYP molecules that catalyze this reaction, their individual contribution ratios are unknown. The previous studies have shown that CYP3A4 has the highest contribution ratio at roughly 71%, 2) based on which a model unit reaction system using as reagent the recombinant CYP3A4 of an Escherichia coli expression system has been established. Next, the inhibitory effects of 29 drugs reported to induce gynecomastia on the 2-hydroxylation of E2 were investigated. Thirteen drugs of them showed high inhibition on the 2-hydroxylation, 3) but the rest 16 showed slight or no inhibition. Thus, gynecomastia by these drugs could not be explained in terms of the inhibition of the 2-hydroxylation alone.The possible candidates for the inhibition mechanism include drug inhibition of the estrogen production system involved in the estrogen pool (aromatase pathway), the estrogen regeneration system (sulfatase pathway), and/or 17b-hydroxysteroid dehydrogenase (17b-HSD) and its related systems. As a result of studies on these possibilities, it was found that drugs that induce gynecomastia may also inhibit the 17b-HSD system as well as the phase I reaction of E2. 3,4)The above results indicate that the phase II reaction (conjugation) must also be taken into consideration as one of the reaction systems affecting the estrogen pool (Fig. 1). The phase II reaction of E2 in humans consists primarily of the 3-or 17-glucuronidation by UDP-glucuronosyltransferase (UGT). UGT is divided into two subfamilies, UGT1 and UGT2, and each subfamily has some isoforms.5) UGT1A1 and UGT2B7 catalyze the 3-and 17-glucuronidation of E2, respectively, yielding estradiol 3-glucuronide (E2-3G) and estradiol 17-glucuronide (E2-17G).6) Because the two UGTs have low substrate specificity and are involved in the glucuronidation of drugs and other xenobiotic substances, [7][8][9][10][11] the interactions between E2 and drugs are predicted.This study was conducted for the purpose of investigating the inhibitory ef...

show abstract

Section: Discussionsupporting

confidence: 66%

Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Satoh¹,

Tomikawa

Takanashi

et al. 2004

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…However, several lines of investigation described below seem to support the in vivo inhibitory effect of ketoconazole. First, the K i values of ketoconazole for the inhibition of M-3-G and M-6-G formation were close to the K i (80 M) seen for the inhibition of zidovudine glucuronidation (Sampol et al, 1995). In addition, fluconazole, another azole drug, is known to affect the bioavailability of zidovudine in vivo (Kiang et al, 2005).…”

Section: Discussionsupporting

confidence: 56%

“…If this is true, the following may be the reason codeine synergistically enhances the inhibitory effect of ketoconazole: that is, ketoconazole may bind to its specific site to modulate efficacy and/or specificity in the interaction of opioid and its association site. Ketoconazole is suggested to be a competitive inhibitor of zidovudine UGT in human liver microsomes (Sampol et al, 1995) (Table 1). Since zidovudine glucuronidation is catalyzed by UGT2B7 (Court et al, 2003), it is reasonable to consider that ketoconazole also directly inhibits UGT2B7-catalyzed zidovudine glucuronidation.…”

Section: Discussionmentioning

confidence: 99%

“…Although diclofenac is a potent inhibitor of codeine glucuronidation in vitro (K i ϭ 7.9 M; Ammon et al, 2000), it has only a low ability to inhibit the glucuronidation of morphine by human liver microsomes (IC 50 ϭ approximately 500 M; King et al, 2001). In contrast, using human liver microsomes, it has been reported that ketoconazole, a P450 inhibitor , competitively inhibits the glucuronidation of the UGT2B7 substrate zidovudine with a K i of 80 M (Sampol et al, 1995). A recent study by Yong et al (2005), also using human liver microsomes, showed that ketoconazole inhibited UGT1A-mediated glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38) and cDNA-expressed UGT1A isoforms.…”

mentioning

confidence: 99%

“…A recent study by Yong et al (2005), also using human liver microsomes, showed that ketoconazole inhibited UGT1A-mediated glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38) and cDNA-expressed UGT1A isoforms. Since glucuronidation of zidovudine is catalyzed by human liver microsomal UGT (Sampol et al, 1995), it is conceivable that UGT2B7 is inhibited by ketoconazole. However, there are no data that demonstrate the direct inhibition of UGT2B7 by ketoconazole.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Udp-Glucuronosyltransferase 2b7-Catalyzed Morphine Glucuronidation by Ketoconazole: Dual Mechanisms Involving a Novel Noncompetitive Mode

Takeda¹,

Kitajima²,

Ishii³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Glucuronidation of morphine in humans is predominantly catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). Since our recent research suggested that cytochrome P450s (P450s) interact with UGT2B7 to affect its function [Takeda S et al. (2005) Mol Pharmacol 67:665-672], P450 inhibitors are expected to modulate UGT2B7-catalyzed activity. To address this issue, we investigated the effects of P450 inhibitors (cimetidine, sulfaphenazole, erythromycin, nifedipine, and ketoconazole) on the UGT2B7-catalyzed formation of morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G). Among the inhibitors tested, ketoconazole was the most potent inhibitor of both M-3-G and M-6-G formation by human liver microsomes. The others were less effective except that nifedipine exhibited an inhibitory effect on M-6-G formation comparable to that by ketoconazole. Neither addition of NADPH nor solubilization of liver microsomes affected the ability of ketoconazole to inhibit morphine glucuronidation. In addition, ketoconazole had an ability to inhibit morphine UGT activity of recombinant UGT2B7 freed from P450. Kinetic analysis suggested that the ketoconazole-produced inhibition of morphine glucuronidation involves a mixedtype mechanism. Codeine potentiated inhibition of morphine glucuronidation by ketoconazole. In contrast, addition of another substrate, testosterone, showed no or a minor effect on ketoconazole-produced inhibition of morphine UGT. These results suggest that 1) metabolism of ketoconazole by P450 is not required for inhibition of UGT2B7-catalyzed morphine glucuronidation; and 2) this drug exerts its inhibitory effect on morphine UGT by novel mechanisms involving competitive and noncompetitive inhibition.

show abstract

Glucuronidation of olanzapine by cDNA‐expressed human UDP‐glucuronosyltransferases and human liver microsomes

Línnet¹

2002

Human Psychopharmacology

View full text Add to dashboard Cite

Olanzapine is a widely used, newer antipsychotic agent, which is metabolized by various pathways: hydroxylation and N-demethylation by cytochrome P450, N-oxidation by flavin monooxygenase and direct glucuronidation. In vivo studies have pointed towards the latter pathway as being of major importance. Accordingly, the glucuronidation reaction was studied in vitro using cDNA-expressed human UDP-glucuronosyltransferase (UGT) enzymes and a pooled human liver microsomal preparation (HLM). Glucuronidated olanzapine was determined by HPLC after acid or enzymatic hydrolysis. The following UGT-isoenzymes were screened for their ability to glucuronidate olanzapine: 1A1, 1A3, 1A4, 1A6, 1A9, 2B7 and 2B15. Only UGT1A4 was able to glucuronidate olanzapine obeying saturation kinetics. The K(m) value was 227 micromol/l (SE 43), i.e. of the same order of magnitude as for other psychotropic drugs, and the V(max) value was 2370 pmol/(min mg) (SE 170). Glucuronidation was also mediated by the HLM preparation, but a saturation level was not reached. The olanzapine glucuronidation reaction was inhibited by several drugs known as substrates for UGT1A4, e.g. amitriptyline, trifluoperazine and lamotrigine. Thus, competition for glucuronidation by UGT1A4 represents a possibility for drug-drug interactions in subjects receiving several of these psychotropic drugs at the same time. Whether such possible interactions are of any clinical importance may await further studies in patients.

show abstract

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Cited by 23 publications

References 14 publications

Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Inhibition of Udp-Glucuronosyltransferase 2b7-Catalyzed Morphine Glucuronidation by Ketoconazole: Dual Mechanisms Involving a Novel Noncompetitive Mode

Glucuronidation of olanzapine by cDNA‐expressed human UDP‐glucuronosyltransferases and human liver microsomes

Contact Info

Product

Resources

About