Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E-3174

McCrea, Jacqueline B.; Cribb, Alastair E.; Rushmore, Tom; Osborne, Barbara A.; Gillen, Lisa; Lo, Mimi; Waldman, Scott A.; Bjornsson, Thorir D.; Spielberg, Stephen P.; Goldberg, Michael R.

doi:10.1016/s0009-9236(99)70114-1

Cited by 70 publications

(33 citation statements)

References 24 publications

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“…However, some initial clinical studies have suggested that there is little difference in overall diclofenac oral clearance, 4Ј-hydroxy diclofenac plasma concentrations, or the urinary excretion of total 4Ј-hydroxy diclofenac (free ϩ conjugated) among different CYP2C9 genotypes (Shimamoto et al, 2000;Morin et al, 2001;Yasser et al, 2001). These clinical data on diclofenac do not seem to correlate with what has been observed for other CYP2C9 substrates such as warfarin, losartan, and tolbutamide where the pharmacokinetic (and as a result pharmacodynamic) characteristics appear closely linked to the CYP2C9 genotype (Aithal et al, 1999;McCrea et al, 1999). Our data on the metabolism of diclofenac in HLMs may provide a possible explanation for these discrepancies.…”

Section: Discussionmentioning

confidence: 85%

Extrapolation of Diclofenac Clearance from in Vitro Microsomal Metabolism Data: Role of Acyl Glucuronidation and Sequential Oxidative Metabolism of the Acyl Glucuronide

Kumar

Samuel

Subramanian

et al. 2002

J Pharmacol Exp Ther

149

105

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Diclofenac is eliminated predominantly (ϳ50%) as its 4Ј-hydroxylated metabolite in humans, whereas the acyl glucuronide (AG) pathway appears more important in rats (ϳ50%) and dogs (Ͼ80 -90%). However, previous studies of diclofenac oxidative metabolism in human liver microsomes (HLMs) have yielded pronounced underprediction of human in vivo clearance. We determined the relative quantitative importance of 4Ј-hydroxy and AG pathways of diclofenac metabolism in rat, dog, and human liver microsomes. Microsomal intrinsic clearance values (CL int ϭ V max /K m ) were determined and used to extrapolate the in vivo blood clearance of diclofenac in these species. Clearance of diclofenac was accurately predicted from microsomal data only when both the AG and the 4Ј-hydroxy pathways were considered. However, the fact that the AG pathway in HLMs accounted for ϳ75% of the estimated hepatic CL int of diclofenac is apparently inconsistent with the 4Ј-hydroxy diclofenac excretion data in humans. Interestingly, upon incubation with HLMs, significant oxidative metabolism of diclofenac AG, directly to 4Ј-hydroxy diclofenac AG, was observed. The estimated hepatic CL int of this pathway suggested that a significant fraction of the intrahepatically formed diclofenac AG may be converted to its 4Ј-hydroxy derivative in vivo. Further experiments indicated that this novel oxidative reaction was catalyzed by CYP2C8, as opposed to CYP2C9-catalyzed 4Ј-hydroxylation of diclofenac. These findings may have general implications in the use of total (free ϩ conjugated) oxidative metabolite excretion for determining primary routes of drug clearance and may question the utility of diclofenac as a probe for phenotyping human CYP2C9 activity in vivo via measurement of its pharmacokinetics and total 4Ј-hydroxy diclofenac urinary excretion.In vitro drug metabolism systems, especially liver microsomes, offer tremendous promise as a tool in drug discovery and development to make human pharmacokinetic projections for potential drug candidates (Obach et al., 1997;Obach, 1999). These systems allow for lead selection based on metabolism data in human tissue that seem more relevant to the human in vivo situation than the in vivo animal models. The popularity of liver microsomes, in comparison with other in vitro systems such as hepatocytes and liver slices, stems from the ease of their preparation, use, and long-term storage and viability. However, the use of liver microsomes for extrapolation of in vivo clearance suffers from a number of limitations such as nonspecific binding of compounds to microsomal components, reduced rates of metabolism because of potential product inhibition kinetics, and the difficulties in examining conjugative metabolism (e.g., glucuronidation) in microsomal incubations. These limitations lead to frequent underprediction of in vivo clearance from microsomal metabolism data (Houston and Carlile, 1997;Obach, 1999). There have been only a few attempts to extrapolate in vivo clearance from microsomal metabolism data for compound...

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Section: Discussionmentioning

confidence: 85%

Extrapolation of Diclofenac Clearance from in Vitro Microsomal Metabolism Data: Role of Acyl Glucuronidation and Sequential Oxidative Metabolism of the Acyl Glucuronide

Kumar

Samuel

Subramanian

et al. 2002

J Pharmacol Exp Ther

149

105

View full text Add to dashboard Cite

show abstract

“…Four studies comprising 60 healthy volunteers have investigated the relationship between CYP2C9 status and losartan/E-3174 plasma pharmacokinetics after a single losartan dose Yasar et al, 2002;Lee et al, 2003b;Sekino et al, 2003). The CYP2C9*3 allele was associated with decreased production of E-3174, with homozygotes converting Ͻ1% of a dose to E-3174 (McCrea et al, 1999;Yasar et al, 2002). In individuals homozygous and heterozygous for CYP2C9*3, mean AUCs of E-3174 were ϳ7 and 50% of the wild type, respectively .…”

Section: B Cyp2c9mentioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…49 Losartan, a potent antagonist of AT 1 , is metabolized via CYP2C9 and CYP3A4 to its active metabolite, E-3174. 50 McCrea et al 51 described a case of a patient showing a minimal conversion of losartan to its active metabolite who was diagnosed as phenotypic PM for CYP2C9 and carrier of the CYP2C9*3 variant allele. Likewise, in a study of 39 healthy volunteers, the CYP2C9*3 allele was shown to be associated with decreased formation of E-3174.…”

Section: B-blockersmentioning

confidence: 99%