Tolbutamide, Flurbiprofen, and Losartan as Probes of CYP2C9 Activity in Humans

Divisions of Pharmacotherapy, CB# 7360, Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 02/2003; 43(1):84-91. DOI: 10.1177/0091270002239710
Source: PubMed


The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxytolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism.

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    Full-text · Book · Sep 2014
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    • "Losartan (LOS) is a selective angiotensin II receptor antagonist that is widely used in clinical settings to treat hypertension and manage heart failure [1] [2]. Losartan can be metabolized by CYP2C9 and is also used to evaluate CYP2C9 catalytic activity in vitro and in vivo [3] [4]. Previous reports revealed that the genetic polymorphism of CYP2C9 significantly altered losartan oxidation in vitro , and most of the alleles encode defective CYP2C9 [5] [6]. "
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    Full-text · Article · Jul 2014 · International journal of clinical pharmacology and therapeutics
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    • "Data from in vitro studies suggested that CYP3A4 and CYP2C9 are involved in the metabolism of losartan to its active metabolite, E-3174. However, in vivo studies inferred that the CYP2C9 is the major metabolic enzyme of losartan in humans (Lee et al., 2003; Yasar et al., 2001). Previous reports revealed that defective alleles of CYP2C9, such as CYP2C9*2, *3 and *13, exhibit reduced activity in vitro and in vivo, and can reduce the transformation of losartan to E3174 in vivo (Bae et al., 2011; Cabaleiro et al., 2013; Maekawa et al., 2009). "
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    Full-text · Article · Jul 2013 · Xenobiotica
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