Prevalence of CYP2C19 and CYP3A4 in poor metabolizers among inhabitants of Tlaxcala, Mexico

We recently described the presence of the P450 isozymes, CYP2C19 and CYP3A4 among ultra-extensive metabolizers in a Mexican Population from Jalisco state. We found 6% and 11% of poor metabolizers of CYP2C19 and CYP3A4, respectively. As different regions of Mexico differ in the genetic admixture, we now report results from subjects of Tlaxcala state, which has a higher Amerindian population than the state of Jalisco. Thirteen healthy volunteers participated in the study. They received 20 mg of omeprazole (Losec, AstraZeneca) orally. The study had the approval of the Ethics Committee of the Hospital Regional #14 del IMSS in Guadalajara, Mexico. Omeprazole and its metabolites were determined 3 hours after drug administration. A validated HPLC method was employed. The metabolic indexes were measured as omeprazole/hydroxyomeprazol and omeprazol/omeprazole sulphone for 2C19 and 3A4 respectively. No ultra-extensive metabolizers were detected. Poor metabolizers were 31% for 2C19 and 45% for 3A4. These values are much higher than those described in other populations (Fisher exact test: p=0.015 and p<0.001, respectively). These results are surprising for the Tlaxcala group, and could be a result of the sample size, and the differences in genetic admixture of this population. Our findings suggest that a larger study may be warranted to further validate population genotyping

Prevalence of CYP2C19 and CYP3A4 in poor metabolizers among inhabitants of Tlaxcala, Mexico

We recently described the presence of the P450 isozymes, CYP2C19 and CYP3A4 among ultra-extensive metabolizers in a Mexican Population from Jalisco state. We found 6% and 11% of poor metabolizers of CYP2C19 and CYP3A4, respectively. As different regions of Mexico differ in the genetic admixture, we now report results from subjects of Tlaxcala state, which has a higher Amerindian population than the state of Jalisco. Thirteen healthy volunteers participated in the study. They received 20 mg of omeprazole (Losec, AstraZeneca) orally. The study had the approval of the Ethics Committee of the Hospital Regional #14 del IMSS in Guadalajara, Mexico. Omeprazole and its metabolites were determined 3 hours after drug administration. A validated HPLC method was employed. The metabolic indexes were measured as omeprazole/hydroxyomeprazol and omeprazol/omeprazole sulphone for 2C19 and 3A4 respectively. No ultra-extensive metabolizers were detected. Poor metabolizers were 31% for 2C19 and 45% for 3A4. These values are much higher than those described in other populations (Fisher exact test: p=0.015 and p<0.001, respectively). These results are surprising for the Tlaxcala group, and could be a result of the sample size, and the differences in genetic admixture of this population. Our findings suggest that a larger study may be warranted to further validate population genotyping

Phenotype of CYP2C19 and CYP3A4 by determination of omeprazole and its two main metabolites in plasma using liquid chromatography with liquid-liquid extraction.

We present a new simple and reliable HPLC method for measuring omeprazole and its two main metabolites in plasma. This can be used for studying CYP2C19 and CYP3A4 genetic polymorphisms using omeprazole as the probe drug. Omeprazole, hydroxyomeprazole and omeprazole sulfone were extracted from plasma samples with phosphate buffer and dichloromethane-ether (95:5). HPLC separation was achieved using an Ultrasphere ODS C(18) (Beckman) column. The mobile phase was acetonitrile-phosphate buffer (24:76, pH 8), containing nonylamine at 0.015%. Retention times were 9.5 min for omeprazole, 3.25 min for hydroxyomeprazole, 7.4 min for omeprazole sulfone and 6.27 min for internal standard (phenacetine). Detection (UV at 302 nm) of analytes was linear in the range from 96 to 864 ng/ml. This is useful for calculating metabolic index for CYP2C19 and CYP3A4 in adults and children. This method is stable, reproducible, improves resolution and has practical advantages such as low cost.Copyright 2002 Elsevier Science B.V

CYP2C19- and CYP3A4-Dependent Omeprazole Metabolism in West Mexicans

Omeprazole has been used as a drug probe for CYP2C19, but no systematic data are available for Mexican populations. The aim of this study was to evaluate the phenotype frequencies of the CYP2C19 polymorphism in West Mexicans. Besides omeprazole, sulfone was measured to evaluate CYP3A4 after administration of the 20-mg dose to 127 healthy volunteers. Logarithms of metabolic indexes of omeprazole/hydroxyomeprazole for CYP2C19 and omeprazole/omeprazole sulfone for CYP3A4 had trimodal distributions. Five subjects (4%) had a log CYP2C19 metabolic index below -0.9, suggesting an ultra-extensive phenotype. Poor metabolizers (log metabolic index > 0.6) were 6%. For CYP3A4, 11 subjects (9%) were below -0.3 of the log metabolic index. The log metabolic index of omeprazole/omeprazole sulfone was above the antimode of 0.6 for 11% of this population. The mean log metabolic index of CYP3A4 extensive metabolizers (80%) was 0.166, which seems to be higher than the data described for Caucasians and lower than that for Asians. © 2003 the American College of Clinical Pharmacology

Metabolism of omeprazole after two oral doses in children 1 to 9 months old

Proton pump inhibitors (PPIs) have been used recently for gastrointestinal esophageal reflux disease (GERD) in children older than one year with good results [1,2]. However, the pharmacokinetics of PPIs have not been studied in children less than two years old. The aim of our study was to evaluate the frequency of the main phenotypes of the metabolizing enzymes CYP2C19 and CYP3A4 in Mexican infants. Our results indicate no significant difference between the 0.5 and the 1.5 mg/kg doses. The percentage of CYP2C19- poor metabolizers was 17% in babies below 4 months and was not detected in children above 3 months. When a combined CYP2C19- and CYP3A4- phenotype was estimated, omeprazole levels were significantly higher in poor metabolizers than in extended metabolizers. The percentage of ultra-extensive metabolizers in children older than 3 months were 20% and 33% for CYP2C19 and CYP3A4 respectively, compared to only 6% and 9% respectively, in babies between 1 and 3 months old. In general children, under 4 months had higher omeprazole levels and an immature metabolism. Studies in children older than 2 years old have showed similar pharmacokinetics to adults. For children between 1 month old and up to 9 months, we suggest the use of the 0.5 mg/kg dose, since it prevents accumulation in poor metabolizers, caution is recommended to identify ultra-fast metabolizers, but this would require new studies