Traore, A. N.Potgieter, N.Kinnear, C. J.Mashilo, Maphepele Sara2026-02-032026-02-032025-09-05Mashilo, M.S. 2025. The pharmacogenetics and pharmacokinetics of ADME polymorphisms in-drug-sensitive and drug-resistant tuberculosis patients from rural healthcare facilities in the Vhembe District of Limpopo (South Africa). . .https://univendspace.univen.ac.za/handle/11602/3146Ph. D. (Life Sciences)(Microbiology)Department of Biochemistry and MicrobiologyBACKGROUND Tuberculosis (TB) is the second leading cause of death after the recent Coronavirus (COVID-19) pandemic. The rate of TB mortality remains high due to the emergence and spread of drug-resistant TB (DR-TB), which includes multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Although TB is curable, the most common side effect associated with the use of anti-TB drugs globally is hepatotoxicity. This observation has been associated with the host genetic variation in the genes involved in drug absorption, distribution, metabolism, and excretion (ADME). The African population has been reported to have a high genetic diversity, yet their genomic information on the genetic contribution to TB and treatment is understudied. AIM OF THE STUDY This study sought to investigate the pharmacogenetic analysis of ADME polymorphisms in TB patients from rural healthcare facilities in the Vhembe District, Limpopo province of South Africa. METHODOLOGY Thirty-five TB outpatients were recruited from various healthcare facilities in Vhembe District. In this study, data and samples were collected from August 2022 to December 2023. Interviews were conducted to collect socio-demographic information and other factors related to TB, and samples (Sputum, urine, and blood) of the participants. DNA isolated from sputum was used to confirm (Anyplex MTB/NTM) and determine the extent of the MDR/XDR-TB using Allplex™ MTB/MDR/XDRe kit from Seegene, and the Zymo kit was used for blood DNA extraction. The whole genome sequencing was achieved by Next-generation sequencing (NGS) technique to analyse the SNPs involved in drug ADME to understand the risk associated with treatment failures and predisposition to anti-TB induced toxicity on only seven genomic DNA (gDNA) samples, and untargeted metabolomics were used to evaluate the metabolites in the urine of the TB/MDR-TB patients. RESULTS Among the 35 participants, 54,3% (19/35) were females. The ages of the participants ranged from 23 to 72 years. The estimated prevalence of DR-MTB was 11.4% (4/35). Unemployment constituted 65% (23/35) of the participants’ status. Fifty-one percent (18/35) of the patients were co-infected with HIV. In total, the co-infections included MTB+NTM (40%, 14/35), MDR-MTB+NTM (5,7%, 2/35), XDR-MTB+NTM (2,9%, 1/35) and XDR-MTB+HIV (2.9%, 1/35). ANOVA analysis across groups identified 42 significantly altered metabolites (p < 0.05), where 2149 were annotated from a spectrum of 4191. The metabolomics resulted in 5 pathways, including i) One carbon pool by folate, ii) Folate biosynthesis, iii) Sphingolipid metabolism, iv) Tryptophan metabolism, and v) Fatty acid biosynthesis. Pharmacogenomics revealed a high prevalence of variants in UGT1A9 (94), ABCB1 (88), SLCO1B1 (69) and CYP24A1 (49) genes affecting drug metabolism and transport. NAT2 genotyping predicted diverse acetylator phenotypes with slow and intermediate acetylators predominating, suggesting variable isoniazid metabolism and potential differences in treatment efficacy and toxicity risk. CONCLUSION The study's findings underscore the urgent need for targeted strategies in addressing MTB and DR-TB. The high prevalence of co-infection, particularly NTM+DR-MTB, and HIV+DR-MTB should be a primary focus in MTB control in the Vhembe district. The significant proportion of unemployment among TB patients and late healthcare consultation were identified as key risk factors. Strategies should prioritise education on TB co-infection diagnosis/ treatment and address unemployment, as these are crucial areas where interventions can significantly impact the health of the individuals and the overall public health in this region. Integration of metabolomic and genetic analyses highlights complex host-pathogen interactions in DS-TB and DR-TB, underscoring metabolic pathway disruptions and genetic polymorphisms that influence drug response. Therefore, this initiative is crucial for assessing the likelihood of drug resistance, toxicity, and treatment failure. Therefore, these findings emphasize the need for personalised medicine approaches to optimize anti-TB therapy in genetically diverse populations, thus preventing individuals predisposed to ADR attributable to anti-TB drugs. Further validation and functional studies are warranted to translate these insights into clinical practice.1 online resource (xiii, 109 leaves)enUniversity of VendaADMEDrug-resistant tuberculosisNGSNTMPharmacogeneticsPharmakokineticsTuberculosisThesisMashilo MS. The pharmacogenetics and pharmacokinetics of ADME polymorphisms in-drug-sensitive and drug-resistant tuberculosis patients from rural healthcare facilities in the Vhembe District of Limpopo (South Africa). []. , 2025 [cited yyyy month dd]. Available from:Mashilo, M. S. (2025). <i>The pharmacogenetics and pharmacokinetics of ADME polymorphisms in-drug-sensitive and drug-resistant tuberculosis patients from rural healthcare facilities in the Vhembe District of Limpopo (South Africa)</i>. (). . Retrieved fromMashilo, Maphepele Sara. <i>"The pharmacogenetics and pharmacokinetics of ADME polymorphisms in-drug-sensitive and drug-resistant tuberculosis patients from rural healthcare facilities in the Vhembe District of Limpopo (South Africa)."</i> ., , 2025.TY - Thesis AU - Mashilo, Maphepele Sara AB - BACKGROUND Tuberculosis (TB) is the second leading cause of death after the recent Coronavirus (COVID-19) pandemic. The rate of TB mortality remains high due to the emergence and spread of drug-resistant TB (DR-TB), which includes multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Although TB is curable, the most common side effect associated with the use of anti-TB drugs globally is hepatotoxicity. This observation has been associated with the host genetic variation in the genes involved in drug absorption, distribution, metabolism, and excretion (ADME). The African population has been reported to have a high genetic diversity, yet their genomic information on the genetic contribution to TB and treatment is understudied. AIM OF THE STUDY This study sought to investigate the pharmacogenetic analysis of ADME polymorphisms in TB patients from rural healthcare facilities in the Vhembe District, Limpopo province of South Africa. METHODOLOGY Thirty-five TB outpatients were recruited from various healthcare facilities in Vhembe District. In this study, data and samples were collected from August 2022 to December 2023. Interviews were conducted to collect socio-demographic information and other factors related to TB, and samples (Sputum, urine, and blood) of the participants. DNA isolated from sputum was used to confirm (Anyplex MTB/NTM) and determine the extent of the MDR/XDR-TB using Allplex™ MTB/MDR/XDRe kit from Seegene, and the Zymo kit was used for blood DNA extraction. The whole genome sequencing was achieved by Next-generation sequencing (NGS) technique to analyse the SNPs involved in drug ADME to understand the risk associated with treatment failures and predisposition to anti-TB induced toxicity on only seven genomic DNA (gDNA) samples, and untargeted metabolomics were used to evaluate the metabolites in the urine of the TB/MDR-TB patients. RESULTS Among the 35 participants, 54,3% (19/35) were females. The ages of the participants ranged from 23 to 72 years. The estimated prevalence of DR-MTB was 11.4% (4/35). Unemployment constituted 65% (23/35) of the participants’ status. Fifty-one percent (18/35) of the patients were co-infected with HIV. In total, the co-infections included MTB+NTM (40%, 14/35), MDR-MTB+NTM (5,7%, 2/35), XDR-MTB+NTM (2,9%, 1/35) and XDR-MTB+HIV (2.9%, 1/35). ANOVA analysis across groups identified 42 significantly altered metabolites (p < 0.05), where 2149 were annotated from a spectrum of 4191. The metabolomics resulted in 5 pathways, including i) One carbon pool by folate, ii) Folate biosynthesis, iii) Sphingolipid metabolism, iv) Tryptophan metabolism, and v) Fatty acid biosynthesis. Pharmacogenomics revealed a high prevalence of variants in UGT1A9 (94), ABCB1 (88), SLCO1B1 (69) and CYP24A1 (49) genes affecting drug metabolism and transport. NAT2 genotyping predicted diverse acetylator phenotypes with slow and intermediate acetylators predominating, suggesting variable isoniazid metabolism and potential differences in treatment efficacy and toxicity risk. CONCLUSION The study's findings underscore the urgent need for targeted strategies in addressing MTB and DR-TB. The high prevalence of co-infection, particularly NTM+DR-MTB, and HIV+DR-MTB should be a primary focus in MTB control in the Vhembe district. The significant proportion of unemployment among TB patients and late healthcare consultation were identified as key risk factors. Strategies should prioritise education on TB co-infection diagnosis/ treatment and address unemployment, as these are crucial areas where interventions can significantly impact the health of the individuals and the overall public health in this region. Integration of metabolomic and genetic analyses highlights complex host-pathogen interactions in DS-TB and DR-TB, underscoring metabolic pathway disruptions and genetic polymorphisms that influence drug response. Therefore, this initiative is crucial for assessing the likelihood of drug resistance, toxicity, and treatment failure. Therefore, these findings emphasize the need for personalised medicine approaches to optimize anti-TB therapy in genetically diverse populations, thus preventing individuals predisposed to ADR attributable to anti-TB drugs. Further validation and functional studies are warranted to translate these insights into clinical practice. DA - 2025-09-05 DB - ResearchSpace DP - Univen KW - ADME KW - Drug-resistant tuberculosis KW - NGS KW - NTM KW - Pharmacogenetics KW - Pharmakokinetics KW - Tuberculosis LK - https://univendspace.univen.ac.za PY - 2025 T1 - The pharmacogenetics and pharmacokinetics of ADME polymorphisms in-drug-sensitive and drug-resistant tuberculosis patients from rural healthcare facilities in the Vhembe District of Limpopo (South Africa) TI - The pharmacogenetics and pharmacokinetics of ADME polymorphisms in-drug-sensitive and drug-resistant tuberculosis patients from rural healthcare facilities in the Vhembe District of Limpopo (South Africa) UR - ER -