The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.

Sm, Sim; Back, DJ; Breckenridge, AM

doi:10.1111/j.1365-2125.1991.tb05607.x

Cited by 59 publications

(36 citation statements)

References 15 publications

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“…The optimized model was used to generate population predictions of plasma concentration vs. time profiles for a virtual population of healthy adults ( n = 1,000) created using the PK‐Sim population module 25. Interindividual variability of UGT2B7 expression was assumed to have log‐normal distribution with a geometric SD of 1.34 26. Fluconazole's unbound fraction ( f u ) was assumed to have a normal distribution with an arithmetic SD of 7% 27, 28.…”

Section: Methodsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Watt

Cohen‐Wolkowiez

Barrett

et al. 2018

CPT Pharmacom & Syst Pharma

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Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants. Next, an ECMO compartment was added to the PBPK model and parameterized using data from a previously published ex vivo study. Simulations using the final ECMO PBPK model reasonably characterized observed PK data in infants on ECMO, and the model was used to derive dosing in children on ECMO across the pediatric age spectrum. This approach can be generalized to other forms of extracorporeal life support (ECLS), such as dialysis.

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Section: Methodsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Watt

Cohen‐Wolkowiez

Barrett

et al. 2018

CPT Pharmacom & Syst Pharma

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“…However, the Km for ZDV glucuronidation is high (3.7 mM) and many studies on drug-drug interactions with ZDV [17,18] have used very high concentrations (1 to 10 mm). Since such concentrations are well in excess of plasma concentrations it may be considered that comparison between in vitro and in vivo data are highly speculative.…”

Section: Resultsmentioning

confidence: 99%

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

Sampol¹,

Lacarelle²,

Rajaonarison³

et al. 1995

Brit J Clinical Pharma

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Zidovudine (ZDV) is extensively metabolised by the liver to an inactive glucuronide (GZDV). Since ZDV is often administered with antimycotic drugs, we studied the effect of six systemic antifungal agents on the in vitro glucuronidation of ZDV by human liver microsomes. 5-fluorocytosine and itraconazole had no inhibitory effect whereas amphotericine B, ketoconazole, miconazole and fluconazole inhibited in vitro GZDV formation (Ki values were 0.13, 0.08, 0.18 and 1.4 mm respectively).

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“…Glucuronidation activities of estradiol 3␤-glucuronidation (UGT1A1), trifluoperazine glucuronidation (UGT1A4), and propofol glucuronidation (UGT1A9) were obtained from the manufacturer. AZT glucuronidation (UGT2B7) was measured based on a previously reported method (Sim et al, 1991). Correlation analysis was conducted, and p Ͻ 0.05 was considered statistically significant.…”

Section: Methodsmentioning

confidence: 99%

Regioselective Glucuronidation of Tanshinone IIa after Quinone Reduction: Identification of Human UDP-Glucuronosyltransferases, Species Differences, and Interaction Potential

Wang¹,

Hao²,

Zhu³

et al. 2010

Drug Metab Dispos

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ABSTRACT:We have previously identified that the predominant metabolic pathway for tanshinone IIa (TSA) in rat is the NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated quinone reduction and subsequent glucuronidation. The present study contributes to further research on its glucuronidation enzyme kinetics, the identification of human UDP-glucuronosyltransferase (UGT) isoforms, and the interaction potential with typical UGT substrates. A pair of regioisomers (M1 and M2) of reduced TSA glucuronides was found from human, rat, and mouse, whereas only M1 was found in dog liver S9 incubations. The overall glucuronidation clearance of TSA in human liver S9 was 11.8 ؎ 0.8 l/min/mg protein, 0.7-, 0.8-, and 3-fold of that in the mouse, rat, and dog, respectively. Using intrinsic clearance M2/M1 as a regioselective index, opposite regioselectivity was found between human (0.7) and mouse (1.3), whereas no significant regioselectivity was found in rat. In a sequential metabolism system, by applying human liver cytosol as an NQO1 donor combined with a screening panel of 12 recombinant human UGTs, multiple UGTs were found involved in the M1 formation, whereas only UGT1A9 and, to a very minor extent, UGT1A1 and UGT1A3 contributed to the M2 formation. Further enzyme kinetics, correlation, and chemical inhibition studies confirmed that UGT1A9 played a major role in both M1 and M2 formation. In addition, TSA presented a potent inhibitory effect on the glucuronidation of typical UGT1A9 substrates propofol and mycophenolic acid, with an IC 50 value of 8.4 ؎ 1.8 and 8.9 ؎ 1.9 M, respectively. This study will help to guide future studies on characterizing the NQO1-mediated reduction and subsequent glucuronidation of other quinones.Quinones are a large group of compounds ubiquitous in nature and characterized with great biological, pharmacological, and/or toxicological significance. Humans are unavoidably exposed to many endogenous quinones such as coenzyme Q, vitamin K, oxidized products of endogenous phenols, and some xenobiotic quinones from foods, environmental pollutants, and drugs. The carbonyl group in the quinone structure is often a determining functional factor for their activities (Oppermann, 2007). For example, the quinone/hydroquinone interconversion of coenzyme Q plays an important role in the electron transport involved in cellular respiration, and the one-electron and/or two-electron reduction of the quinone carbonyl group-triggered redox cycle also largely explains the pharmacological or toxicological activities of many quinones. Note that the quinone carbonyl reduction and subsequent conjugation constitute the major biotransformation and metabolic elimination pathway of most quinones. Therefore, the biotransformation study of quinones is essential for understanding their bioactivation, detoxification, and/or inactivation process.Tanshinones are a class of diterpene phenanthrenequinone compounds isolated from the dried root of Salvia miltiorrhiza (Fam. Labiatae), which is a widely used traditional Chinese medicine with w...

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The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.

Cited by 59 publications

References 15 publications

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

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

Regioselective Glucuronidation of Tanshinone IIa after Quinone Reduction: Identification of Human UDP-Glucuronosyltransferases, Species Differences, and Interaction Potential

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