ABSTRACT
Objective: To determine the relationship between Gly64Asp (rs77630697) polymorphism of multidrug and toxin extrusion-1 (MATE-1) and therapeutic response of metformin in Type-2 diabetic patients. Methods: A longitudinal study was conducted at Riphah International Hospital, Islamabad from June 2020 to December 2021. Type-2 diabetic patients (n=200) on metformin monotherapy fulfilling the inclusion criteria were enrolled and followed up till three months. Based on change in HbA1c, they were divided into responders and non-responders. DNA was extracted and genotyping was done by TETRA ARMS PCR. Data was entered and association was analyzed by SPSS 22. Results: Out of 200 participants, 104 were categorized as responders and 96 as non-responders. The genotype and allelic distribution of rs77630697 was significantly different between responders and non-responders. The variant genotype (GG) was most prevalent among the study population and among responders. After follow up of three months, difference in glycemic response was found to be statistically significant (p < 0.05) among three genotypes (GG, GA and AA). The decline in HbA1c was highest in GG genotype with almost two-fold reduction in comparison with GA and AA. Carriers of allele A were significantly associated with impaired response to metformin. Conclusion: The variable therapeutic response to metformin in the responders and non-responders may be contributed to rs77630697 isoform variation of MATE-1.
ABSTRACT
Methimazole (MMI) is a widely used drug for hyperthyroidism. However, its clinical use is associated with hepatotoxicity. Though the precise mechanism of hepatic damage is still far from clear, role of metabolic activation and reactive metabolites have been implicated. The present study was designed to investigate the role of enzyme induction in bioactivation based hepatotoxicity of methimazole in mice. Thirty male mice were randomly divided into five groups. Hepatotoxicity was induced by single intraperitoneal injection of methimazole (1000mg/kg). Pretreatment with rifampicin which is a potent enzyme inducer was carried out for 6 days prior to administration of methimazole. The extent of hepatic damage was determined by measuring serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) along with histopathological grading of liver samples. The elevated levels of biochemical markers by methimazole were potentiated by pretreatment with rifampicin. This potentiation of hepatic injury was also observed in liver histopathological examination. These findings suggest induction of microsomal enzymes as a potentiating factor of methimazole induced hepatotoxicity.
