The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys

Abstract

1. Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12 mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28 L/kg, respectively) with terminal elimination half-life approximately 6 h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension. 2. Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species. 3. Following oral administration to rats, [(14)C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24 h. 4. The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

“…For this analysis, animal lung concentration data were available for anidulafungin (rat), bazedoxifene (rat), chloroquine (3 albino rat studies), favipiravir (monkey), hydroxychloroquine (2 albino rat studies), nitazoxanide (mouse), tamoxifen (rat), cyclosporine (rat), ritonavir (rat), azithromycin (mouse), dolutegravir (mouse), gilteritinib (albino rat), and lopinavir (rat). [23][24][25][26][27][28][29][30][31][32] Agreement between the predicted and measured K p was assessed by simple linear regression and by constructing Bland-Altman plots, the limits of agreement (mean ± 2 SD) were included in these plots as previously described. 33…”

Potential drug–drug interactions between antiretroviral therapy and treatment regimens for multi-drug resistant tuberculosis: Implications for HIV care of MDR-TB co-infected individuals

“…Dolutegravir, an alternative drug to efavirenz or nevirapine in adult first-line ART, although primarily metabolized by UGT, is partially metabolized by CYP3A4/5 (Moss et al, 2015). Although the impact of clofazimine on UTG is not well established, a DTG area under the AUC ratio AUCR (AUCinhibitor/AUCcontrol) of 3.0 was reported, comparable to those reported with lopinavir and other strongly inhibited antiviral agents during co-administration with clofazimine (Sangana et al, 2018).…”

CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor

“…The current study found that CYP1A1 and 1B1-dependent production of DTG metabolites (M1 and M4) were dramatically increased in the lungs of mice treated with TCDD. Interestingly, DTG is highly distributed in the lung after DTG treatment [9]. The high pulmonary exposure to DTG together with the highly induced CYP1A1 and 1B1 in the lung of smokers will increase DTG metabolism, and therefore increase the clearance of DTG.…”

“…In a mass balance study of DTG, the predominant circulating component identified in plasma was DTG, and 31.6% and 64.0% of the administrated dose was recovered in urine and feces, respectively [8]. The most abundant metabolites of DTG were the ether glucuronide followed by a benzylic hydroxylated metabolite and its hydrolytic product [9]. UDP-glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 are the two key enzymes contributing to the ether glucuronidation and benzylic oxidation of DTG, respectively [10].…”