The Metabolism of Artemether-lumefantrine Combination Therapy for Uncomplicated Plasmodium falciparum Malaria in Sudan

Background Artemether-lumefantrine (AL) is the first-line treatment for uncomplicated Plasmodium falciparum malaria in Sudan. Significant inter-individual variability in drug disposition suggests genetic influences on metabolism through cytochrome P450 enzymes. This study aimed to determine allele frequencies of key CYP450 variants affecting AL metabolism in the Sudanese population. Methods Whole exome sequencing data from 55 healthy Sudanese individuals were analyzed for CYP2C8*2 (rs11572103), CYP2C8*3 (rs10509681/rs11572080), CYP2B6*6 (rs3745274), CYP3A4*1B (rs2740574), CYP3A5*3 (rs776746), and CYP3A5*6 (rs10264272) using standard bioinformatics pipelines. Results Allele frequencies were: CYP2C8*2 (8.1%), CYP2C8*3 (4.5%), CYP2B6*6 (35.4%), CYP3A4*1B (0.9%), CYP3A5*3 (20.0%), and CYP3A5*6 (13.6%). The remarkably low CYP3A4*1B frequency contrasts sharply with other African populations (73–79%). High CYP2B6*6 frequency indicates 12.5% of the population are poor metabolizers at elevated risk for artemisinin toxicity. Conclusion Sudan exhibits a unique pharmacogenetic profile with dramatically low CYP3A4*1B and high CYP2B6*6 frequencies. These findings provide crucial insights for optimizing AL therapy and highlight the importance of population-specific pharmacogenetic data for malaria treatment in endemic regions.