Glucuronidation of 3′-azido-3′-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase

Resetar, Andrea; Minick, Douglas J.; Spector, Thomas

doi:10.1016/0006-2952(91)90319-z

Cited by 48 publications

(28 citation statements)

References 49 publications

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“…For the inhibition of AZT upon EFV-G, K i Ͼ K m indicate that the affinity of UGT2B7 for EFV is greater than for AZT, in accordance with the kinetic described above. It is noteworthy that previous K i values for AZT glucuronidation inhibition ranged from 38 M [ethinylestradiol (Herber et al, 1992)] to 47 000 M [sulfisoxazole (Resetar et al, 1991)]. Moreover, kinetic experiments in the absence of bovine serum albumin as performed herein, overestimate K m and underestimate true K i , particularly for substrates of UGT2B7 (Rowland et al, 2007).…”

Section: Downloaded Frommentioning

confidence: 56%

“…The evaluation of the theoretical percent inhibition achievable in vivo at pharmacological concentrations (peak plasma levels) of EFV and AZT was predicted using the equation: i ϭ 100 (Resetar et al, 1991). In this equation, i ϭ percent inhibition, [I] and [S] ϭ EFV and AZT at pharmacological steady-state concentration achieved in plasma, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Glucuronidation of the Antiretroviral Drug Efavirenz by UGT2B7 and an in Vitro Investigation of Drug-Drug Interaction with Zidovudine

et al. 2009

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ABSTRACT:The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is directly conjugated by the UDP-glucuronosyltransferase (UGT) pathway to form EFV-N-glucuronide (EFV-G), but the enzyme(s) involved has not yet been identified. The glucuronidation of EFV was screened with UGT1A and UGT2B enzymes expressed in a heterologous system, and UGT2B7 was shown to be the only reactive enzyme. The apparent K m value of UGT2B7 (21 M) is similar to the value observed for human liver microsomes (24 M), whereas the variant allozyme UGT2B7*2 (Tyr 268 ) displayed similar kinetic parameters. Because 3-azido-3-deoxythymidine (AZT), one of the most current nucleotide reverse transcriptase inhibitors prescribed in combination with EFV, is also conjugated by UGT2B7, the potential metabolic interaction between EFV and AZT has been studied using human liver microsomes. Glucuronidation of both drugs was inhibited by one another, in a concentrationdependent manner. At K m values (25 and 1000 M for EFV and AZT, respectively), EFV inhibited AZT glucuronidation by 47%, whereas AZT inhibited EFV glucuronidation by 23%. With a K i value of 17 M for AZT-glucuronide formation, EFV appears to be one of the most selective and potent competitive inhibitor of AZT glucuronidation in vitro. Moreover, assuming that concentrations of EFV achieved in plasma (C max ‫؍‬ 12.9 M) are in a range similar to its K i value, it was estimated that EFV could produce a theoretical 43% inhibition of AZT glucuronidation in vivo. We conclude that UGT2B7 has a major role in EFV glucuronidation and that EFV could potentially interfere with the hepatic glucuronidation of AZT.Efavirenz [(EFV) (Sustiva); Bristol-Myers Squibb Co., Princeton, NJ] is the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) agent for initial therapy for HIV infection. A typical antiretroviral treatment regimen consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor or an NNRTI. The 2008 IAS-USA guidelines recommend either of two basic threedrug regimens for treatment of antiretroviral-naive patients: 1) EFV plus two NRTIs; or 2) a ritonavir-boosted protease inhibitor (lopinavir, atazanavir, fosamprenavir, darunavir, or saquinavir) plus two NRTIs [tenofovir and emtricitabine; abacavir and lamivudine; or 3Ј-azido-3Ј-deoxythymidine (zidovudine; AZT) and lamivudine] (Hammer et al., 2008). A recent study on HIV-infected adults of Southern Africa further revealed that among patients who began nevirapine-based or EFV-based antiretroviral therapy between January 1998 and September 2004, 1321 of 1822 EFV-treated patients (72.5%) received it in combination with the NRTI pair AZT plus lamivudine (Nachega et al., 2008). Thus, a significant proportion of HIV-infected, highly active antiretroviral therapy-naive adults receive EFV and AZT in combination.A large interpatient variability was found to affect EFV bioavailability (coefficient of variation up to 118%) (Marzolini et al., 2001), which might be explained in part by its extensive metabolism....

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Section: Downloaded Frommentioning

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Glucuronidation of the Antiretroviral Drug Efavirenz by UGT2B7 and an in Vitro Investigation of Drug-Drug Interaction with Zidovudine

et al. 2009

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“…The K m for zidovudine glucuronidation in HLM was reported as 2.4 mM. 42) Similarly, the K m of morphine glucuronidation in HLM is also in the range of only a few mM. 20) Despite such larger K m values, glucuronidation is the major metabolic pathway of morphine and zidovudine.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Ishii

Iida

Miyauchi

et al. 2012

Biological & Pharmaceutical Bulletin

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Morphine is an important drug used to alleviate moderate to severe pain. This opiate is mainly metabolized by glucuronidation to a non-analgesic metabolite, morphine-3-glucuronide (M-3-G) and an active metabolite morphine-6-glucuronide (M-6-G). To understand the modulation of morphine glucuronidation activity by environmental factors, the effect of endogenous and food-derived compounds on morphine uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) in rat and human microsomes was evaluated examining the 50% inhibitory concentration (IC 50 ). The liver microsomes from Sprague-Dawley rats (RLM) and humans (HLM, 150 donors, pooled microsomes) were used as enzyme sources. Of 27 compounds tested, monoterpenoid alcohols, such as borneol and iso-borneol, exhibited a strong inhibitory effect on morphine glucuronidation in rat liver microsomes (RLM), whereas we failed to detect any inhibitory effect of endogenous substances including amino acids and sugars. The substances which have the ability to inhibit the activity in RLM are also inhibitory toward morphine glucuronidation in HLM and UGT2B7 baculosomes. However, the difference was that while the strongest inhibitory effect was observed for iso-menthol in HLM, borneol was the strongest inhibitor of the activity mediated by RLM. Although zidovudine is a typical substrate of UGT2B7, the inhibition of morphine glucuronidation by zidovudine was far weaker than that of monoterpenoid alcohols. These results demonstrate that dietary and supplementary monoterpenoid alcohols modify the pharmacokinetics and pharmacodynamics of morphine through inhibition of UGT2B7.Key words uridine 5′-diphosphate-glucuronosyltransferase; glucuronidation; morphine; borneol; iso-menthol; monoterpenoid alcohol Morphine is an important analgesic for relieving moderate to severe pain (WHO). The major metabolic pathway for morphine is glucuronidation leading to the formation of morphine-3-glucuronide (M-3-G) and morphine-6-glcuronide (M-6-G).1) While M-3-G is a non-analgesic metabolite, M-6-G is a far more potent analgesic than the parent morphine.2) M-3-G is the major metabolite of morphine in many species. However, the ability to form M-6-G varies from species to species, 3) and relatively higher activity was detected in humans 4,5) and guinea pigs.3) Glucuronidation is catalyzed by uridine 5′-diphosphate (UDP)-glucuronosyltrasferase (UGT) which is expressed mainly in the liver and gastro-intestinal tract.6) UGT is a family of enzymes which transfer the glucuronic acid moiety of the co-substrate, UDP-glucuronic acid (UDPGA), to an acceptor substrate.7) Previous studies have suggested that, among UGT isoforms, UGT2B1 and UGT2B7 contribute to morphine glucuronidation in rats and humans, respectively. 8,9)The accelerated action of narcotics is recommended for curing cancer pain because withdrawal symptoms rarely happen even following the opiate treatment of patients with pain.10) However, a problem associated with the clinical use of narcotics is that the mortality of patients due to overdosing ...

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“…The results of the present study show that the hepatic metabolism of ZDV is impaired in patients with mild hepatic dysfunction. The glucuronidation of ZDV is catalyzed by UDP-glucuronosyltransferase (UDPGT) (17). At least five different human UDPGT isozymes are known, and several forms have yet to be adequately characterized (25).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062)

Moore

Raasch

Brouwer

et al. 1995

Antimicrob Agents Chemother

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Glucuronidation of 3′-azido-3′-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase

Cited by 48 publications

References 49 publications

Glucuronidation of the Antiretroviral Drug Efavirenz by UGT2B7 and an in Vitro Investigation of Drug-Drug Interaction with Zidovudine

Glucuronidation of the Antiretroviral Drug Efavirenz by UGT2B7 and an in Vitro Investigation of Drug-Drug Interaction with Zidovudine

Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062)

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