PT - JOURNAL ARTICLE AU - Patel, Mitesh AU - Eberl, H. Christian AU - Wolf, Andrea AU - Pierre, Esaie AU - Polli, Joseph W. AU - Zamek-Gliszczynski, Maciej J. TI - Mechanistic Basis of Cabotegravir–Glucuronide Disposition in Humans AID - 10.1124/jpet.119.258384 DP - 2019 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 269--277 VI - 370 IP - 2 4099 - http://jpet.aspetjournals.org/content/370/2/269.short 4100 - http://jpet.aspetjournals.org/content/370/2/269.full SO - J Pharmacol Exp Ther2019 Aug 01; 370 AB - Cabotegravir, a novel integrase inhibitor under development for treatment and prevention of HIV, is primarily metabolized by UGT1A1 and UGT1A9 to a direct ether glucuronide metabolite. The aim of these studies was to elucidate the mechanistic basis of cabotegravir–glucuronide disposition in humans. Cabotegravir glucuronidation was predominantly hepatic (>95%) with minimal intestinal and renal contribution. Rat liver perfusions demonstrated that cabotegravir–glucuronide formed in the liver undergoes comparable biliary and sinusoidal excretion, consistent with high concentrations of the glucuronide in human bile and urine. Cabotegravir–glucuronide biliary excretion was mediated by MRP2 (not transported by BCRP or P-gp), whereas hepatic basolateral excretion into sinusoidal blood was via both MRP3 (Ft = 0.81) and MRP4 (Ft = 0.19). Surprisingly, despite high urinary recovery of hepatically-formed cabotegravir–glucuronide, metabolite levels in circulation were negligible, a phenomenon consistent with rapid metabolite clearance. Cabotegravir–glucuronide was transported by hepatic uptake transporters OATP1B1 and OATP1B3; however, metabolite clearance by hepatic uptake from circulation was low (2.7% of hepatic blood flow) and unable to explain the minimal systemic exposure. Instead, circulating cabotegravir–glucuronide undergoes efficient renal clearance, where uptake into the proximal tubule would be mediated by OAT3 (not transported by OAT1), and subsequent secretion into urine by MRP2 (Ft = 0.66) and MRP4 (Ft = 0.34). These studies provide mechanistic insight into the disposition of cabotegravir–glucuronide, a hepatically-formed metabolite with appreciable urinary recovery and minimal systemic exposure, including fractional contribution of redundant transporters to any given process based on quantitative proteomics.SIGNIFICANCE STATEMENT The role of membrane transporters in metabolite disposition, especially glucuronides, and as sites of unexpected drug–drug interactions, which alter drug efficacy and safety, has been established. Cabotegravir–glucuronide, formed predominantly by direct glucuronidation of parent drug in liver, was the major metabolite recovered in human urine (27% of oral dose) but was surprisingly not detected in systemic circulation. To our knowledge, this is the first mechanistic description of this phenomenon for a major hepatically-formed metabolite to be excreted in the urine to a large extent, but not circulate at detectable levels. The present study elucidates the mechanistic basis of cabotegravir–glucuronide disposition in humans. Specific hepatic and renal transporters involved in the disposition of cabotegravir–glucuronide, with their fractional contribution, have been provided.