Metabolism and Disposition in Humans of Raltegravir (MK-0518), an Anti-AIDS Drug Targeting the Human Immunodeficiency Virus 1 Integrase Enzyme

Abstract

ABSTRACT:Raltegravir is a potent human immunodeficiency virus 1 (HIV-1) integrase strand transfer inhibitor that is being developed as a novel anti-AIDS drug. The absorption, metabolism, and excretion of raltegravir were studied in healthy volunteers after a single oral dose of 200 mg (200 Ci) of [ 14 C]raltegravir. Plasma, urine, and fecal samples were collected at specified intervals up to 240 h postdose, and the samples were analyzed for total radioactivity, parent compound, and metabolites. Radioactivity was eliminated in substantial amounts in both urine (32%) and feces (51%). The elimination of radioactivity was rapid, since the majority of the recovered dose was attributable to samples collected through 24 h. In extracts of urine, two components were detected and were identified as raltegravir and the glucuronide of raltegravir (M2), and each accounted for 9% and 23% of the dose recovered in urine, respectively. Only a single radioactive peak, which was identified as raltegravir, was detected in fecal extracts; raltegravir in feces is believed to be derived, at least in part, from the hydrolysis of M2 secreted in bile, as demonstrated in rats. The major entity in plasma was raltegravir, which represented 70% of the total radioactivity, with the remaining radioactivity accounted for by M2. Studies using cDNA-expressed UDP-glucuronosyltransferases (UGTs), form-selective chemical inhibitors, and correlation analysis indicated that UGT1A1 was the main UGT isoform responsible for the formation of M2. Collectively, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.HIV-1 is the etiologic agent of AIDS. HIV infection continues to be a major problem with more than 40 million individuals currently infected with the virus worldwide ([UNAIDS] Joint United Nations Programme on HIV/AIDS 2006 Report on the global AIDS epidemic. http://www.unaids.org). The current standard of care for treating HIV infection, called HAART, is a regimen typically consisting of three or more drugs from two or more available classes. Current HAART medications (of which there are Ͼ20) include members from four classes of drugs: nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Although the advent of HAART has significantly reduced AIDS-related morbidity and mortality, it has been estimated that 78% of treatment-naive patients harbor viruses that are resistant to one or more of the three classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors) (Richman, 2001;Little et al., 2002). Because of this factor and issues of tolerability, toxicity, and patient noncompliance due to the rigorous drug administration schedules, there is a critical need for new HIV therapies capable of addressing the deficiencies inherent with currently used drugs.Integrase is one of the three HIV-1 enzymes required for viral replication (Esposito and Cr...

In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor

“…This interaction with DTG is likely the combined effect of UGT and CYP3A4 induction. This is consistent with etravirine and efavirenz causing modest decreases (20-40%) in the pharmacokinetics of raltegravir, a sensitive UGT substrate (Kassahun et al, 2007;Iwamoto et al, 2008). Support for a role of CYP3A4 induction was demonstrated by coadministration of the potent CYP3A4 inhibitors lopinavir/ritonavir or darunavir/ritonavir that counteracted the decrease in DTG exposure by etravirine (Song et al, 2011c).…”

Differentially Stimulated CD4+T Cells Display Altered Human Immunodeficiency Virus Infection Kinetics: Implications for the Efficacy of Antiviral Agents

“…The differences observed in HIV kinetics led us to examine the sensitivity of the above cell populations to antiretroviral drugs targeting the early stages in the viral life cycle. To address this, cells were treated with zidovudine (AZT) (10 M), efavirenz (EFV) (0.1 M) (4,23,33), or the integrase inhibitors 118-D-24 (80 M) (26) and raltegravir (50 nM), which was recently approved for clinical use (8)(9)(10), at various time points postinfection. The inhibition of viral replication was assessed by quantifying intracellular p24 Gag levels 48 h postinfection.…”

Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

“…The major circulating entity in plasma was the parent compound (69% of the total drug-related material in plasma), whereas most of the drug-related material in urine was accounted for by the glucuronide derivative (72% of the drug-related material in urine). In feces, only parent compound was detected, but it is likely that a good proportion of the raltegravir detected in feces is derived from hydrolysis of the glucuronide derivative secreted in bile as observed in preclinical species (Kassahun et al, 2007).…”

“…In vivo and in vitro studies using isoform selective chemical inhibitors and cDNA-expressed UGTs showed that UGT1A1 is the primary enzyme responsible for the formation of raltegravir-glucuronide (87) (Merck & Co, 2007;Kassahun et al, 2007). In vitro studies demonstrate that raltegravir is not a substrate for cytochrome P450 (CYP) enzymes and does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce 3A4 (Iwamoto et al, 2008).…”

“…The only metabolite detected in humans was the phenolic hydroxyl glucuronide (87), and this metabolite does not have antiviral activity (Kassahun et al, 2007) (Figure 16). In a human ADME study, ∼51 and 32% of a radiolabeled raltegravir dose (parent and metabolite) was excreted in the feces and urine, respectively.…”