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Introduction Thiopurine S-methyltransferase (TPMT) methylates clinically relevant thiopurine drugs most of which are noted for adverse reactions in certain users, largely due to polymorphisms in the TPMT gene. Aim This study investigated the prevalence of functionally relevant TPMT alleles in the Nigerian population. Material and methods One hundred eighty unrelated subjects consisting of 123 males and 57 females from the main Nigerian ethnicities (44 Igbo, 101 Yoruba, 23 Hausa and 12 from other minor ethnic groups) were genotyped for TPMT*2 , *3B , *3C and *4 alleles using the iPLEX genotyping assay technique. The genotype calls were validated with Sanger sequencing in a random set of samples and the acquired data were assessed for Hardy–Weinberg equilibrium using the Fisher's exact test. Results and discussion Defective TMPT alleles were found in individuals representing 10% of the study population. TPMT*3C constituted 9.4% (95% CI, 5.6–14.7) of all alleles detected, with one homozygote and 17 heterozygotes recorded. The prevalence of the TPMT*3C allele in the population conformed with Hardy–Weinberg equilibrium. TPMT*2 , 3B and *4 were, however, not detected in the population. Conclusions TPMT*3C was the only defective allele identified in Nigerians and may hence be the major underlying genetic contributor to adverse reactions due to thiopurine drugs in the population. [ABSTRACT FROM AUTHOR]

Background: CYP1A2 and CYP2A6 are polymorphic drugmetabolising enzymes that are also implicated in the activation of procarcinogens in humans. Some of their alleles and haplotypes, often varied in prevalence across populations, are thought to influence activity despite the known contribution of environmental factors. This study assessed the potential influence of some genetic variants of CYP1A2 and CYP2A6 on metabolic phenotypes in Nigerians. Methods: Genomic DNA was extracted from blood samples of 100 healthy, unrelated subjects for whom CYP1A2 and CYP2A6 phenotypes had previously been determined, alongside an additional 80 other individuals for whom phenotype data were unavailable. The samples were screened for CYP1A2 (*1C,*1D,*1E,*1F, *3,*4,*6,*7) and CYP2A6 (*9,*11,*17) alleles using the Sequenom MassARRAY platform for some alleles and direct Sanger sequencing for others. The genetic data acquired were subsequently analysed for haplotypes and assessed for concordance with phenotypes. Results: All five CYP1A2 haplotypes (CYP1A2*1F, 1J, 1N, 1L, 1W) identified in the Nigerian population were not significantly predictive of metabolic phenotypes. Heterozygous CYP1A2*1J carriers and homozygous CYP1A2*1W carriers showed statistically insignificant decrease in CYP1A2 activity. The CYP2A6*9/*17 genotype was, however, significantly associated with the CYP2A6-poor metabolic phenotype, whereas CYP2A6*9 or CYP2A6*17 alone did not show any such association. CYP2A6*11 was not detected in the population. Conclusions: Our findings suggest that CYP1A2 alleles or haplotypes were not predictive of metabolic phenotypes in the Nigerian population. Carriers of CYP2A6*9/*17 genotype are likely to be poor metabolisers of CYP2A6 substrates and may experience adverse reactions or poor efficacy while using drugs metabolised mainly by CYP2A6. [ABSTRACT FROM AUTHOR]

• Varied disposition imparts on the tolerance and safety of quinine, and thus constitutes a major limiting consideration for its dosing in uncomplicated malaria. Utilizing a population approach, the effect of body weight and infection status on disposition parameters of quinine were evaluated in Nigerian subjects. • A reversal of infection-induced changes in volume of distribution and clearance after 48 h of chronic quinine administration was noted. • It is hypothesized that a downward review of quinine regimen post-48 h of chronic administration, in the event of complete parasitaemia clearance, might be a useful approach in enhancing tolerance and safety. The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans. Using a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes. Concentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm. All datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h–1, 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients. The study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients. [ABSTRACT FROM AUTHOR]