An increase in urinary primaquine and a reduction in urinary primaquine-5,6-orthoquinone in the Thai population with CYP2D6 reduced enzyme function
Waritda Pookmanee,
Siriwan Thongthip,
Mathirut Mungthin,
Chonlaphat Sukasem,
Jeeranut Tankanitlert,
Pajaree Chariyavilaskul,
Supeecha Wittayalertpanya
Affiliations
Waritda Pookmanee
Interdisciplinary Program in Pharmacology, Graduate School, Chulalongkorn University, Bangkok, Thailand; Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Medical Depot Division, Royal Thai Army Medical Department, Bangkok, Thailand
Siriwan Thongthip
Maha Chakri Sirindhorn Clinical Research Center under the Royal Patronage, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Mathirut Mungthin
Department of Pharmacology, Phramongkutklao College of Medicine, Bangkok, Thailand
Chonlaphat Sukasem
Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center, Ramathibodi Hospital, Bangkok, Thailand; Pharmacogenomics and Precision Medicine, The Preventive Genomics & Family Check-up Services Center, Bumrungrad International Hospital, Bangkok, Thailand
Jeeranut Tankanitlert
Department of Pharmacology, Phramongkutklao College of Medicine, Bangkok, Thailand
Pajaree Chariyavilaskul
Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Corresponding author. Ph.D. Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Supeecha Wittayalertpanya
Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Corresponding author. Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Objectives: Primaquine is metabolized by the cytochrome P450-2D6 enzyme (CYP2D6) to an active primaquine-5,6-orthoquinone (POQ). No relationships of CYP2D6 polymorphisms with the pharmacokinetics of primaquine and POQ were reported in the Thai population. Methods: We evaluated the genetic distribution of CYP2D6 in 345 Thai army populations together with the pharmacokinetic profiles of primaquine and POQ in plasma and urine (n = 44, descriptive data are presented in median (range)). All dose-related pharmacokinetic parameters were normalized by primaquine dose per body weight before statistical analysis. Results: CYP2D6*10 was the allele observed with the highest frequency (56.62%) corresponding to CYP2D6*10/*10 (32.94%) and CYP2D6*1/*10 (27.94%) genotypes. CYP2D6 intermediate metabolizers (CYP2D6 IM) were found in 44.41% of the cohort and had an increase in the cumulative amount of primaquine excreted (CAE) in urine compared to normal metabolizers of CYP2D6 (CYP2D6 NM); (CYP2D6 IM vs. CYP2D6 NM: 2444 (1697–3564) vs. 1757 (1092–2185) μg/mg/kg, p = 0.039), a reduction in urine CAE of POQ (CYP2D6 IM vs CYP2D6 NM: 115 (46–297) vs. 318 (92–498) μg/mg/kg, p = 0.047) and a reduction in the POQ/primaquine CAE ratio in urine (CYP2D6 IM vs. CYP2D6 NM: 0.06 (0.01–0.11) vs. 0.16 (0.06–0.26), p = 0.009). No significant differences were found in the pharmacokinetic profiles of plasma primaquine and POQ. Conclusions: The CYP2D6 polymorphisms influenced the changes in primaquine and POQ that were noticeable in the urine, supporting the role of the CYP2D6 gene testing before drug administration.
