Dolutegravir metabolism: impact of genetic variations on uridine diphosphate glucuronosyltransferase subfamilies

Dolutegravir (DTG) is a key drug used to treat human immunodeficiency virus type-1 (HIV-1) infections. Adverse events (AEs) of DTG treatment, including headache, anxiety, depression, insomnia, and abnormal dreams, are influenced by sex, body weight, age, and serum bilirubin levels. DTG is mainly metabolised by members of the uridine diphosphate glucuronosyltransferase 1A subfamilies (UGT1As), especially UGT1A1.Some studies suggest a relationship between <i>UGT1A1</i> variants and AEs. The aim of this study was to identify UGT1A isoforms that exhibit DTG glucuronidation activity and determine the relationship between <i>UGT1A</i> variants and DTG glucuronidation <i>in vitro</i>.UGT1A1, UGT1A3, UGT1A9, and UGT1A10 exhibited DTG glucuronidation activity, of which UGT1A1 was the most active. Furthermore, variants of these isoforms showed decreased DTG glucuronidation activity. The different variants of <i>UGT1A</i>s, such as UGT1A1.6, UGT1A1.7, UGT1A1.35, UGT1A1.63, UGT1A3.5, UGT1A9.2, UGT1A10M59I, and UGT1A10T202I, showed reduced glucuronidation activity towards DTG in comparison with the wild-type <i>UGT1A</i>s.This study elucidates the relationship between <i>UGT1A</i> variants and the levels of glucuronidation associated with each variant.Checking for <i>UGT1A</i>s may be helpful in predicting potential toxicities and adverse effects related to DTG treatment.