Drug glucuronidation in humans

Miners, John O.; Mackenzie, Peter I.

doi:10.1016/0163-7258(91)90065-t

Cited by 325 publications

(204 citation statements)

References 217 publications

Supporting

Mentioning

201

Contrasting

Order By: Relevance

“…Despite the magnitude of these changes, the clinical consequences of impaired glucuronidation of DHA in MI in humans are dicult to predict. Glucuronidation is a high-capacity conjugation reaction (Mulder, 1992), but few drugs are metabolized exclusively by this pathway (Miners & MacKenzie, 1991) and, to the best of our knowledge, none of these has been the subject of detailed evaluation in human MI. Recent studies from our laboratories have shown that DHAglucuronide also is the principal metabolite of DHA in human liver microsomes (unpublished data, Ilett et al).…”

Section: Discussionmentioning

confidence: 99%

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

Batty

Ilett

Edwards

et al. 1998

British J Pharmacology

View full text Add to dashboard Cite

1 The clearance of dihydroartemisinin (DHA) in control and malaria-infected (MI) rats was investigated using the isolated perfused rat liver (IPRL) model and hepatic microsomal studies. 2 In the recirculating IPRL, clearance of DHA was reduced from a mean (s.d.) of 8.2+1.8 ml min 71 in controls (n=8) to 6.0+1.0 ml min 71 in MI (n=8; P50.01). Clearance in control livers was similar to the perfusion¯ow rate, suggesting a high hepatic extraction ratio for DHA. 3 Single-pass IPRL studies in controls (n=8) showed that DHA bioavailability at 1.3, 8 and 38 mM was 0.026+0.020, 0.043+0.025 and 0.14+0.06, respectively (P50.001 for 8 mM vs 38 mM). In MI livers (n=5), DHA bioavailability at 8 and 38 mM was 0.18+0.07 and 0.40+0.08, respectively (P=0.002). Bioavailability was higher in the MI group than in controls (P=0.01 at 8 mM and P50.001 at 38 mM). DHA-glucuronide was the sole biliary metabolite. 4 Hepatic microsomal studies of DHA-glucuronide formation showed a signi®cantly lower V max , but no signi®cant change in K m , in MI compared to control livers (n=6). Intrinsic metabolic clearance (V max /K m ) was higher in control than in MI livers (5.2+1.3 and 2.5+1.4 ml min 71 mg 71 , respectively; P=0.006). 5 These studies demonstrate that DHA has a high, concentration-dependent hepatic extraction ratio that is reduced by 20 ± 30% in the P. berghei rodent malaria model. The impaired hepatic clearance of DHA in MI is attributable to a reduction in intrinsic metabolic clearance.

show abstract

Section: Discussionmentioning

confidence: 99%

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

Batty

Ilett

Edwards

et al. 1998

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Individual UGT isozymes and substrate specificity A wide variety of drugs and other xenobiotics are known to be glucuronidated in the human body, and UGT isozymes show broad overlapping substrate specificity toward these chemicals (Miners and Mackenzie, 1991;Tukey and Strassburg, 2000). Thus, while an endogenous substrate like bilirubin is almost exclusively glucuronidated via UGT1A1, acetaminophen is a phenolic substrate of several UGT1A and 2B isozymes (Court et al, 2001).…”

Section: The Ugt Superfamilymentioning

confidence: 99%

“…The effect of UGT polymorphisms on the prevalence rates of various types of cancer has also been studied. The substrate specificity, tissue-specific expression and relevance in different disease states of the UGT isozymes have been reviewed elsewhere (Burchell and Coughtrie, 1989;Miners and Mackenzie, 1991;Tukey and Strassburg, 2000;Burchell, 2003;Wells et al, 2004). With new polymorphisms being frequently discovered in UGT genes, this chapter aims at providing an updated and comprehensive review of genetic variation in the UGT gene family, and its relevance to cancer.…”

Section: Introductionmentioning

confidence: 99%

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

View full text Add to dashboard Cite

The uridine diphosphoglucuronosyltransferases (UGTs) belong to a superfamily of enzymes that catalyse the glucuronidation of numerous endobiotics and xenobiotics. Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure. Genetic polymorphisms have been identified for almost all the UGT family members. A wide variety of anticancer drugs, dietary chemopreventives and carcinogens are known to be conjugated by members of both UGT1A and UGT2B subfamilies. This review examines in detail each UGT isozyme known to be associated with cancer and carcinogenesis. The cancer-related substrates for several UGTs are summarized, and the functionally relevant genetic polymorphisms of UGTs are reviewed. A number of genotype-phenotype association studies have been carried out to characterize the role of UGT pharmacogenetics in several types of cancer, and these examples are discussed here. In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk.

show abstract

“…25,26) The majority of UGT isoforms show distinct, but overlapping, substrate specificities. [25][26][27] Although EE 2 has also been shown to be a substrate for UGT1A1, 28) other isoforms may also catalyze EE 2 3-glucuronidation. 26,29) Genetic polymorphism has been reported for UGT1A1 and other isoforms.…”

Section: Discussionmentioning

confidence: 99%

Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver

Shiraga

Niwa

Ohno

et al. 2004

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Ethynylestradiol (EE 2 ) is commonly used as the major estrogenic component in many oral contraceptive formulations. Orme et al. 1) reported that EE 2 is metabolized by multiple pathways, and there is a large interindividual variability in the routes and rates of metabolism of EE 2 in humans. In addition, marked interindividual differences in the pharmacokinetic parameters of EE 2 have been reported.1) The reported systemic bioavailability of orally ingested EE 2 ranges from 20 to 65%. 1) Factors that could affect oral clearance of a drug include absorption from the gastrointestinal tract, protein binding, intrinsic hepatic clearance, hepatic blood flow, and renal clearance. Urinary excretion of unchanged EE 2 was very low, 2) suggesting that EE 2 is mainly eliminated by metabolism. The 2-hydroxylation of EE 2 is mainly catalyzed by CYP3A, CYP2C, and CYP2E enzymes, 3,4) and this route is one of the main metabolic pathways in humans.5,6) Additionally, sulfation and glucuronidation also play important roles in the metabolism of EE 2 . EE 2 -3-glucuronide and EE 2 -3-sulfate are eliminated into the gastrointestinal tract, hydrolyzed by gut bacteria to EE 2 , and subsequently reabsorbed. Rifampicin, an inducer of CYP3A, has been reported to significantly increase the oral clearance of EE 2 .7) This interaction is thought to reflect the significant contribution of CYP3A enzymes to the metabolism of EE 2 . It is well known that there are large interindividual differences in the expression levels and catalytic activities of CYP3A enzymes in human liver. 8)Patki et al. 9) indicated that the intrinsic clearance of triazolam, a CYP3A substrate, and CYP3A protein in human liver are reduced in the elderly.In vitro studies are useful for clarifying the role of respective enzymes on the systemic drug clearance. Plasma concentrations of EE 2 achieved during normal therapy are very low (Ͻ2 nM).7) However, most previous in vitro studies used substantially high EE 2 substrate concentrations (Ͼ10 mM). A recent study using human hepatocytes in vitro at a substrate concentration of 1 nM demonstrated that the major EE 2 metabolites are direct conjugates, with hydroxylation representing minor pathways, and suggested that the production of EE 2 -3-sulfate was increased by pretreatment of hepatocytes with rifampicin.10) The initial rate of conjugate formation was reported to be EE 2 -3-sulfateϾEE 2 -3-glucuronide in human hepatocytes. 10) In the current study, we investigated interindividual variability of the 2-hydroxylation, 3-glucuronidation, and 3-sulfation of EE 2 using human liver microsomes and cytosol in the presence of the respective cofactors. Additionally, interindividual variability of the relative contribution of CYP3A to the 2-hydroxylation of EE 2 in human liver microsomes was estimated from the degree of inhibition by ketoconazole, a potent inhibitor of CYP3A. All enzyme activities were measured at an EE 2 substrate concentration of 0.1 mM, which is under a nearly linear condition (Ͻ1/23 of K m values for the respectiv...

show abstract

Drug glucuronidation in humans

Cited by 325 publications

References 217 publications

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver

Contact Info

Product

Resources

About