title: Phenotyping and genotyping of CYP2C19 using comparative metabolism of proguanil in sickle-cell disease patients and healthy controls in Nigeria.
abstract: Polymorphic expression of metabolic enzymes have been identified as one of the key factors responsible for the interindividual/ethnic/racial variability in drug metabolism and effect. In Nigeria, there is a disproportionately high incidence of sickle-cell disease (SCD), a condition characterized by painful crisis frequently triggered by malaria. Proguanil, a substrate of the polymorphic CYP2C19, is a chemoprophylactic antimalarial drug widely used among SCD patients in Nigeria. This study aimed to conduct a comparative CYP2C19 phenotyping among SCD patients and healthy controls and to compare the results with those previously reported. One hundred seventy-seven unrelated subjects comprising 131 SCD patients and 46 non-SCD volunteers were phenotyped. This was carried out by collecting pooled urine samples over 8 h following PG administration. Proguanil and its major CYP2C19-dependent metabolites were measured by high-performance liquid chromatography. Metabolic ratios (MRs) were computed and employed in classifying subjects into poor or extensive metabolizers. Among SCD group, 130 (99.2%) were extensive metabolizers (EMs) and 1 (0.8%) was poor metabolizer (PM) of PG, while 95.7 and 4.3% non-SCDs were EMs and PMs, respectively. MRs ranged from 0.02 to 8.70 for SCD EMs and from 0.22 to 8.33 for non-SCD EMs.Two non-SCDs with MRs of 18.18 and 25.76 and the SCD with MR of 16.77 regarded as PMs had earlier been genotyped as CYP2C19*2/*2. Poor metabolizers of proguanil in SCD patients are reported for the first time. Regardless of clinical significance, a difference in metabolic disposition of proguanil and CYP2C19 by SCDs and non-SCDs was established.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry Faculty of Pharmacy Olabisi Onabanjo University Sagamu Nigeria; Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Ibadan Ibadan Nigeria.
authors.forename: Olufunmilayo E
authors.initials: OE
authors.lastname: Adejumo
authors.affiliation: Department of Haematology College of Medicine University of Ibadan Ibadan Nigeria.
authors.forename: Taiwo R
authors.initials: TR
authors.lastname: Kotila
authors.affiliation: Genetic and Bioethics Unit Institute of Advanced Medical Research and Training (IMRAT) College of Medicine University of Ibadan Ibadan Nigeria.
authors.forename: Adeyinka G
authors.initials: AG
authors.lastname: Falusi
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Technology Faculty of Pharmacy University of Lagos Lagos Nigeria.
authors.forename: Boladale O
authors.initials: BO
authors.lastname: Silva
authors.affiliation: Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Ibadan Ibadan Nigeria.
authors.forename: Jacinta N
authors.initials: JN
authors.lastname: Nwogu
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry Faculty of Pharmacy Olabisi Onabanjo University Sagamu Nigeria; National Center for Natural Product Research School of Pharmacy University of Mississippi Oxford Mississippi United States.
authors.forename: Pius S
authors.initials: PS
authors.lastname: Fasinu
authors.affiliation: Department of Pharmaceutical Chemistry Faculty of Pharmacy University of Ibadan Ibadan Nigeria; Genetic and Bioethics Unit Institute of Advanced Medical Research and Training (IMRAT) College of Medicine University of Ibadan Ibadan Nigeria.
authors.forename: Chinedum P
authors.initials: CP
authors.lastname: Babalola
keywords: CYP2C19; genetic polymorphism; proguanil; sickle‐cell disease