Association between Food/UGT2B7 Polymorphisms and Pharmacokinetics/Pharmacodynamics Properties of Indapamide in Healthy Humans

Abstract

Indapamide is an effective and safe antihypertensive medication showing a beneficial effect in combination with other antihypertensive agents regarding morbidity and mortality. A comparative study was performed under fasting and fed conditions to investigate the effect of food and selected single nucleotide polymorphisms in the uridine diphosphate glucuronyl transferase (UGT2B7) gene on the pharmacokinetics and pharmacodynamics behavior of indapamide 1.5 mg sustained release. Forty-nine healthy volunteers aged 18–55 years were randomized into two groups; 25 volunteers were administered indapamide under fasting conditions and 24 under fed conditions. Genotyping of the UGT2B7 rs7438135 and rs11740316 was done before commencing the study using predesigned TaqMan assays. Results showed that food independently decreased the value of indapamide’ Tmax by 5.5 h and increased the value of Cmax by 8.7 ng/mL. On the other hand, all genetic variants of both UGT2B7 SNPs had no significant impact on the values of Tmax, Cmax, and AUC0–t; however, it was found that rs11740316 variant AG was correlated with a 2.8 h lower MRTinf. Finally, BMI positively correlated with longer MRTinf. It was concluded that none of rs7438135, rs11740316, or food had a significant impact on the pharmacodynamic properties. Food had a modest impact on indapamide Cmax and Tmax values, while there were unremarkable differences in safety and efficacy.

Identification of a Sonically Activated Degrader of Methionine Adenosyltransferase 2A by an in Silico Approach Assisted with the Hole–Electron Analysis

“…The effects of H3 on the activities of major enzymes in the liver were further determined. As shown in Table , H3 displayed moderate inhibition to cytochrome P450 isoforms (SI, Figure S13) and uridine glucuronyl transferases (SI, Figure S14) when the concentration was higher than 10 μM. Considering the strong enrichment of H3 in the liver, the in vivo use of MAT2A inhibitors may generate a certain impact on liver function.…”

“…The effects of H3 on the activities of major enzymes in the liver were further determined. As shown in Table 2, H3 displayed moderate inhibition to cytochrome P450 isoforms 33 (SI, Figure S13) and uridine glucuronyl transferases 34 (SI, Figure S14) when the concentration was higher than 10 μM.…”

Pharmacogenetic Variants Associated with Fluoxetine Pharmacokinetics from a Bioequivalence Study in Healthy Subjects

“…These have been researched thoroughly in the past [ 42 ], aiming for a better understanding of the efficacy of antidepressants from the PD perspective. Even though they seem important in fluoxetine PK, the role of PK-related proteins in drug PD is multifactorial, and medication response still cannot be associated purely with single gene variations, as has been explored and evidenced in similar studies for other therapeutic classes [ 43 ].…”