Background And Aim: Losartan is metabolized by polymorphic CYP2C9 to E‐3174. Our aim was to evaluate the pharmacokinetics of losartan and E‐3174 in relation to the CYP2C9 genotype.Methods: A 50‐mg oral dose of losartan was given to 22 Swedish volunteers with different CYP2C9 genotypes. Losartan and E‐3174 were analyzed by HPLC in plasma and urine samples collected up to 24 hours after drug intake. Furthermore, losartan and E‐3174 were analyzed in 8‐hour urine samples collected from 17 Spanish subjects after a single oral dose of 25 mg losartan.Results: The maximum plasma concentration of E‐3174 was significantly (P < .05) lower in the CYP2C9*1/*3 (n = 5) and CYP2C9*2/*3 (n = 4) groups compared with the CYP2C9*1/*1 (n = 6) and CYP2C9*1/*2 (n = 3) groups and extremely low in 1 subject with the CYP2C9*3/*3 genotype. The ratio of the total losartan area under the plasma concentration–time curve (AUC) to the total E‐3174 AUC (AUC_losartan/AUC_E‐3174) was higher in the subject with the CYP2C9*3/*3 genotype (30‐fold) and also in the CYP2C9*1/*3 and *2/*3 groups (approximately 2‐ and 3‐fold, respectively) compared with the CYP2C9*1/*1 group. The plasma ratios correlated significantly with the 0‐ to 8‐hour urinary losartan/E‐3174 ratios. Among the total of 39 subjects, the urinary ratio was significantly higher in subjects with the CYP2C9*1/*3 (n = 10) and *2/*3 (n = 4) genotypes than in those with the CYP2C9*1/*1 genotype (n = 11; P < .01) and approximately 40‐fold higher in subjects with the CYP2C9*3/*3 genotype (n = 3).Conclusion: The CYP2C9*3 allele was shown to be associated with decreased formation of E‐3174 from losartan. The significant differences between genotypes in plasma and urine losartan/E‐3174 ratios and the good correlation between the plasma and urine ratios suggest that the losartan/E‐3174 ratio in 0‐ to 8‐hour urine specimens may serve as a phenotyping assay for CYP2C9 activity. Further studies in larger populations will be required to establish this.Clinical Pharmacology & Therapeutics (2002) 71, 89–98; doi: 10.1067/mcp.2002.121216

The role of certain drug metabolizing enzymes in cardiotoxicity, such as CYP2D6 for thioridazine, has been suggested. Risperidone has been shown to inhibit the delayed rectifier leading to lengthening of cardiac repolarization. The heart-rate corrected QT (QTc) interval lengthening has been reported in psychiatric patients receiving risperidone under steady-state conditions. CYP2D6 is involved in the metabolism of risperidone to 9-hydroxy (OH)-risperidone. CYP2C9 enzyme is also involved in the metabolism of several psychotropic drugs, although there are no data about its implication in risperidone metabolism. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and plasma concentrations of risperidone and 9-OH-risperidone on the QTc interval in patients under steady-state conditions. The relevance of CYP2D6 and CYP2C9 genotypes on risperidone metabolism was also analysed. Thirty-five White European psychiatric patients receiving risperidone monotherapy were studied. QTc interval was longer ( p < 0.05) in subjects with one active CYP2D6 gene compared to those with two. The number of CYP2D6 active genes was related to the dose-corrected plasma concentration of risperidone ( p < 0.05), the active moiety (risperidone plus 9-OH-risperidone) ( p < 0.05) and the risperidone/9-OH-risperidone ratio ( p < 0.05). CYP2C9 genotypes were not related to plasma concentrations of risperidone or 9-OH-risperidone, nor QTc interval. The results suggest that CYP2D6 , but not CYP2C9 , may be related to QTc lengthening during treatment with risperidone. The effect of the CYP2D6 genotype in risperidone metabolism is also shown.

Our group has previously show that interindividual variability in CYP2D6 hydroxylation capacity was related to personality differences in cognitive social anxiety. Thus, we aimed to analyze whether this relationship between personality and CYP2D6 phenotype and genotype was found in a similar population of healthy volunteers from a different latitude and culture by using the same methodology. A total of 253 university students and staff from Havana Psychiatric Hospital and Calixto García Medical School in Cuba completed the Karolinska Scales of Personality (KSP), and were evaluated on debrisoquine hydroxylation capacity and CYP2D6 genotypes. KSP scores were compared between four groups, divided according to their CYP2D6 metabolic capacity: one of poor and three of extensive metabolizers. Furthermore, KSP scores were compared between another four different groups divided according to their number of CYP2D6 active genes: zero, one, two, and more than two. In Cubans, the differences in cognitive social anxiety-related personality traits across the four CYP2D6 hydroxylation capacity groups were strikingly similar to those found in Spaniards. These differences also came out to be significant for psychic anxiety (p = 0.02) and socialization (p = 0.02). The same pattern of results obtained for the subscales of psychic anxiety, socialization, psychasthenia and inhibition of aggression with regard to phenotype in both the Cuban and Spanish studies were seen with regard to CYP2D6 genotypes. Corroborating these results further strengthens evidence of the relationship between CYP2D6 metabolic capacity and personality. In this population of healthy Cuban volunteers, the CYP2D6 hydroxylation capacity was related to the degree of anxiety and socialization. These results support the postulated reduction of serotonin in CYP2D6 poor metabolizers, which may be associated with a cluster of behavioral traits (e.g., anxiety, impulsivity). Thus, research is warranted to determine CYP2D6 functional implications for interindividual differences in vulnerability to neuropsychiatric diseases and drug response.