Losartan and E3174 Pharmacokinetics
Study Objective: To determine if differences in the pharmacokinetics of losartan and its pharmacologically active E3174 metabolite exist among individuals expressing the cytochrome P450 (CYP) 2C9*1/*1, *1/*2, and *1/*3 genotypes.
Design: Single-dose pharmacokinetic study.
Setting: University general clinical research center.
Subjects: Fifteen healthy volunteers, five from each genotype: CYP2C9*1/*1, *1/*2, and *1/*3.
Intervention: A single oral dose of losartan 50 mg.
Measurements and Main Results: Plasma and urine samples were collected for 24 hours, and losartan and E3174 pharmacokinetic data were compared across the three genotypes. Orthostatic blood pressure was measured over 12 hours after dosing. No significant differences were observed among the three groups in losartan or E3174 area under the plasma concentration-time curve, losartan or E3174 elimination half-life, or losartan oral clearance. A significant association between CYP2C9 genotype and losartan to E3174 formation clearance was observed, such that 50% of the variability was accounted for by the genotype. No significant relationship between that genotype and blood pressure was observed at any time.
Conclusion: Differences in the pharmacokinetics of losartan and its active E3174 metabolite were not observed in healthy subjects with the genotype of CYP2C9*1/*2 and *1/*3 compared with those expressing *1/*1. Alterations in losartan dosing in CYP2C9*1/*2 and *1/*3 individuals does not appear necessary.
Losartan is an orally active, potent angiotensin II receptor subtype 1 (AT1) antagonist approved for treatment of hypertension. The sixth report of the Joint National Committee recommended therapy with angiotensin receptor blockers in hypertensive patients who do not tolerate an angiotensin-converting enzyme inhibitor. However, results from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study in high-risk hypertensive patients with left ventricular hypertrophy showed a significant reduction in risk of cardiovascular outcomes with losartan compared with atenolol, suggesting a substantially increased role for losartan in these patients.
Cytochrome P450 (CYP) 2C9 is an enzyme responsible for the metabolism of numerous drugs and is the primary enzyme responsible for oxidative conversion of losartan to its pharmacologically active carboxylic acid metabolite E3174. It also appears to have a limited role in this metabolic reaction in vitro; however, its role in vivo is less well characterized. The metabolite is a more potent antagonist of the AT1 receptor than losartan and has a larger area under the concentration-time curve (AUC) and longer half-life, suggesting that formation of E3174 by CYP2C9 is necessary for losartan's pharmacologic activity.
Many single nucleotide polymorphisms (SNPs) have been identified in the gene encoding for the CYP2C9 protein, significantly altering the pharmacokinetics and metabolism of certain CYP2C9 substrates. The wild-type allele is designated CYP2C9*1. A cytosine to thymine (C
T) transversion at nucleotide 430 encodes for a cysteine (Cys) substitution at amino acid residue 144, producing the Arg Cys (CYP2C9*2) variant allele. An adenine to cytosine (A
C) transversion at nucleotide 1075 encodes for a leucine (Leu) substitution at amino acid residue 359, producing the Ile Leu (CYP2C9*3) variant allele. The CYP2C9*2 and *3 alleles are associated with lower intrinsic clearance of certain CYP2C9 substrates compared with the *1 allele in vitro; however, the most substantial reductions were observed with the *3 allele.
The CYP2C9*2 and *3 alleles are present in approximately 12% and 7% of Caucasian individuals, respectively, with more than 95% of the population expressing the CYP2C9*1/*1 (~65%), *1/*2 (~20%), and *1/*3 (~11%) genotypes. The *2 and *3 alleles have been identified in substantially lower frequencies in African-American and Asian populations.
The presence of these alleles appears to be important in determining optimal dosages of selected CYP2C9 substrates, including the narrow-therapeutic index agents warfarin and phenytoin. In vitro and in vivo studies also reported that expression of the CYP2C9*2 or *3 allele significantly alters conversion of losartan to E3174, suggesting that CYP2C9*1/*2 and *1/*3 individuals may have significant differences in losartan and E3174 pharmacokinetics compared with *1/*1 persons.
Due to the relatively large number of heterozygote CYP2C9*2 and *3 allele carriers in the population, the primary objective of this investigation was to determine if significant differences in losartan and E3174 pharmaco-kinetics exist in CYP2C9*1/*1, *1/*2, and *1/*3 individuals.
Study Objective: To determine if differences in the pharmacokinetics of losartan and its pharmacologically active E3174 metabolite exist among individuals expressing the cytochrome P450 (CYP) 2C9*1/*1, *1/*2, and *1/*3 genotypes.
Design: Single-dose pharmacokinetic study.
Setting: University general clinical research center.
Subjects: Fifteen healthy volunteers, five from each genotype: CYP2C9*1/*1, *1/*2, and *1/*3.
Intervention: A single oral dose of losartan 50 mg.
Measurements and Main Results: Plasma and urine samples were collected for 24 hours, and losartan and E3174 pharmacokinetic data were compared across the three genotypes. Orthostatic blood pressure was measured over 12 hours after dosing. No significant differences were observed among the three groups in losartan or E3174 area under the plasma concentration-time curve, losartan or E3174 elimination half-life, or losartan oral clearance. A significant association between CYP2C9 genotype and losartan to E3174 formation clearance was observed, such that 50% of the variability was accounted for by the genotype. No significant relationship between that genotype and blood pressure was observed at any time.
Conclusion: Differences in the pharmacokinetics of losartan and its active E3174 metabolite were not observed in healthy subjects with the genotype of CYP2C9*1/*2 and *1/*3 compared with those expressing *1/*1. Alterations in losartan dosing in CYP2C9*1/*2 and *1/*3 individuals does not appear necessary.
Losartan is an orally active, potent angiotensin II receptor subtype 1 (AT1) antagonist approved for treatment of hypertension. The sixth report of the Joint National Committee recommended therapy with angiotensin receptor blockers in hypertensive patients who do not tolerate an angiotensin-converting enzyme inhibitor. However, results from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study in high-risk hypertensive patients with left ventricular hypertrophy showed a significant reduction in risk of cardiovascular outcomes with losartan compared with atenolol, suggesting a substantially increased role for losartan in these patients.
Cytochrome P450 (CYP) 2C9 is an enzyme responsible for the metabolism of numerous drugs and is the primary enzyme responsible for oxidative conversion of losartan to its pharmacologically active carboxylic acid metabolite E3174. It also appears to have a limited role in this metabolic reaction in vitro; however, its role in vivo is less well characterized. The metabolite is a more potent antagonist of the AT1 receptor than losartan and has a larger area under the concentration-time curve (AUC) and longer half-life, suggesting that formation of E3174 by CYP2C9 is necessary for losartan's pharmacologic activity.
Many single nucleotide polymorphisms (SNPs) have been identified in the gene encoding for the CYP2C9 protein, significantly altering the pharmacokinetics and metabolism of certain CYP2C9 substrates. The wild-type allele is designated CYP2C9*1. A cytosine to thymine (C
T) transversion at nucleotide 430 encodes for a cysteine (Cys) substitution at amino acid residue 144, producing the Arg Cys (CYP2C9*2) variant allele. An adenine to cytosine (A
C) transversion at nucleotide 1075 encodes for a leucine (Leu) substitution at amino acid residue 359, producing the Ile Leu (CYP2C9*3) variant allele. The CYP2C9*2 and *3 alleles are associated with lower intrinsic clearance of certain CYP2C9 substrates compared with the *1 allele in vitro; however, the most substantial reductions were observed with the *3 allele.
The CYP2C9*2 and *3 alleles are present in approximately 12% and 7% of Caucasian individuals, respectively, with more than 95% of the population expressing the CYP2C9*1/*1 (~65%), *1/*2 (~20%), and *1/*3 (~11%) genotypes. The *2 and *3 alleles have been identified in substantially lower frequencies in African-American and Asian populations.
The presence of these alleles appears to be important in determining optimal dosages of selected CYP2C9 substrates, including the narrow-therapeutic index agents warfarin and phenytoin. In vitro and in vivo studies also reported that expression of the CYP2C9*2 or *3 allele significantly alters conversion of losartan to E3174, suggesting that CYP2C9*1/*2 and *1/*3 individuals may have significant differences in losartan and E3174 pharmacokinetics compared with *1/*1 persons.
Due to the relatively large number of heterozygote CYP2C9*2 and *3 allele carriers in the population, the primary objective of this investigation was to determine if significant differences in losartan and E3174 pharmaco-kinetics exist in CYP2C9*1/*1, *1/*2, and *1/*3 individuals.
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