ABSTRACT:
INVESTIGATIONS OF N-ACETYL TRANSFERASE(NAT2) POLYMORPHISMS IN PREGNANT WOMEN WITH HIGH SULPHADOXINE CONCENTRATIONS. Malaria remains a major global health challenge, particularly in sub-Saharan Africa, where intermittent preventive treatment in pregnancy with Sulphadoxine-pyrimethamine (IPTp-SP) is a cornerstone of malaria control. However, the variability in Sulphadoxine pharmacokinetics can compromise efficacy and safety. Genetic polymorphisms in the host, such as N-acetyltransferase 2 (NAT2) variants, may underlie this variability. This study investigates NAT2 polymorphisms in a cohort of pregnant women with high plasma Sulphadoxine concentrations, aiming to elucidate their role in drug metabolism and therapeutic outcomes. In this proof-of-concept investigation, genomic DNA was extracted from whole blood samples. NAT2 variants were characterized via Sanger sequencing of PCR-amplified fragments using gene-specific primers. Sequencing reads were aligned to the NAT2 reference sequence to identify single nucleotide polymorphisms (SNPs) and insertion/deletion events. Identified variants were analyzed to determine nucleotide and amino acid changes and to infer acetylator phenotypes (slow, intermediate, or rapid). Simultaneously, plasma Sulphadoxine concentrations were quantified to evaluate the relationship between genotype and drug exposure. The limited cohort revealed a predominance of slow acetylator genotypes, consistent with previous studies in African populations. However, one participant genotyped as a rapid acetylator and another as an intermediate acetylator unexpectedly exhibited high plasma Sulphadoxine concentrations. These findings suggest that NAT2 genotype, in concert with pregnancy-induced physiological changes, may significantly influence Sulphadoxine pharmacokinetics in pregnant women. In summary, this pilot study provides preliminary evidence that NAT2 polymorphisms contribute to inter-individual differences in Sulphadoxine metabolism during pregnancy. These results support the potential utility of PCR-based NAT2 genotyping combined with drug monitoring to optimize IPTp-SP dosing strategies, which could improve maternal and neonatal health outcomes. Although limited by sample size, our findings serve as proof-of-concept and underscore the need for larger-scale investigations to refine malaria prevention and improve maternal and child health.