Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans.

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Castellino S, Moss L, Wagner D, Borland J, Song I, Chen S, Lou Y, Min SS, Goljer I, Culp A, Piscitelli SC, Savina PM

Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans.

Antimicrob Agents Chemother. 2013 Aug;57(8):3536-46. doi: 10.1128/AAC.00292-13. Epub 2013 May 13.

PubMed ID

23669385 [ View in PubMed

]

Abstract

The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [(14)C]dolutegravir at a dose of 20 mg (80 muCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t1/2) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

DrugBank Data that Cites this Article

Drugs

Dolutegravir

Drug Reactions

Reaction
Dolutegravir DB08930 UDP-glucuronosyltransferase 1-1 UDP-glucuronosyltransferase 1-3 UDP-glucuronosyltransferase 1-9 ether glucuronide dolutegravir (M2) DBMET01871	Details
Dolutegravir DB08930 Cytochrome P450 3A4 hydroxilated form of dolutegravir (M3) DBMET01872	Details
hydroxilated form of dolutegravir (M3) DBMET01872 Cytochrome P450 1A1 Cytochrome P450 1B1 2,4- difluorobenzaldehyde (M5 dolutegravir) DBMET03561 hydrolized form of dolutegravir (M1) DBMET01873	Details
Dolutegravir DB08930 defluorinated and gutathione conjugated form of dolutegravir (M4.1) DBMET01874	Details
Dolutegravir DB08930 defluorinated and gutathione conjugated form of dolutegravir (M4.2) DBMET01875	Details

Drug Interactions

Drugs	Interaction
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Dolutegravir Rifampicin	The serum concentration of Dolutegravir can be decreased when it is combined with Rifampicin.