CYP2C19 catalyzed drug metabolism in different populations

Sammanfattning: Metabolism catalyzed by the cytochrome P450 enzyme CYP2C19 varies between individuals, who can be either efficient (EM) or poor metabolizers (PM). In this thesis the metabolism of four different CYP2C19 substrates (citalopram, mephenytoin, omeprazole, and proguanil) was investigated in vivo in Africans (Ethiopians an Tanzanians) an in Swedish is Caucasians. PM lack the enzyme and cannot metabolize drugs that are CYP2C19 substrates. The frequency of PM differs between populations. CYP2C19 activity in Africans matters because the antimalarial prophylactic drug proguanil needs biotransformation by this enzyme to a metabolite, which is active against malaria. Genetic differences in the ability to metabolize drugs are to be expected between populations since humankind has gone through substantial adaptation because of mutations and genetic drift. Inherited properties to metabolize efficiently or poor has been advantageous in different environments, and survival was due to natural selection. This process has created arbitrary ethnic populations. Two screening studies of CYP2C19 activity and two pharmacokinetic studies were performed. All four were in healthy subjects. The CYP2C 19 probe drugs mephenytoin and omeprazole were used for phenotyping in 251 Tanzanians, and mephenytoin together with debrisoquine in 106 Ethiopians living in Sweden. The pharmacokinetics, of the CYP2C19 substrate proguanil was investigated in Tanzanians, and that of citalopram was studied in Swedes. CYP2C19 activity was markedly lower in Tanzanians compared to Asians and Caucasians, despite that the screened mutated alleles known at that time, could not provide an explanation. However, they are unlikely to be the whole explanation. At the time of the beginning of this thesis work, the PM frequency was not extensively studied in Africans, but few reports from few populations indicated a frequency between 5 and 20%. In Tanzanians we found a frequency of 7.5%, and in Ethiopians living in Sweden 4.3%. The decreased CYP2C19 activity shown for mephenytoin and omeprazole hydroxylation in Tanzanians was confirmed with proguanil. The pharmacokinetics of proguanil revealed that it might not be used safely in a Tanzanian population for prophylaxis because too low concentrations of the active metabolite cycloguanil are expected when normal proguanil doses are used. The clinical implications of the slower metabolism in Tanzanians may be the need to prescribe lower doses of drugs that are CYP2C 19 substrates in Tanzanians compared to Caucasians and even Asians. The comparison of mephenytoin and debrisoquine metabolism of Ethiopians living in Sweden with previously published data, by Aklillu et al. and Persson et al. from Ethiopians living in Ethiopia, did not show any statistical difference in CYP2C19 activity in Ethiopians living in Sweden compared to those who live in Ethiopia. Likewise, there was mere a trend toward a difference for the CYP2D6 substrate debrisoquine (p=0.06). CYP2C19 was found to metabolize the S-citalopram, but not R- citalopram in Swedes. Adverse drug effect monitoring in the citalopram study revealed a suggested relationship between high citalopram concentrations and hypomania and yawning. Knowledge of CYP2C 19 metabolism provides information for use and dosage of around twenty drugs used in treatment of malaria, epilepsy, hypertension, peptic ulcer, and in several psychiatric conditions. Therefore these drugs are important and common in all populations all over the world. Expert panel consensus comparing CYP2C19 metabolism in different individuals and populations are warranted to set clinical guidelines regarding the dosage of drugs metabolized by CYP2C 19.