Hepatobiliary Disposition of Atovaquone: A Case of Mechanistically Unusual Biliary Clearance

Patel, Mitesh; Johnson, Marta; Sychterz, Caroline; Lewis, Gareth; Watson, Cory; Ellens, Harma; Polli, Joseph W.; Zamek‐Gliszczynski, Maciej J.

doi:10.1124/jpet.117.247254

Cited by 2 publications

(3 citation statements)

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“…Cell Culture OATP1B1, OATP1B3, OAT1, and OAT3. HEK-MSRII cells overexpressing OATP1B1, OATP1B3, OAT1, and OAT3 were produced using a protocol previously published in the literature (Patel et al, 2018). Briefly, cells were thawed at 37°C and transferred to Dulbecco's modified Eagle's medium and Ham's F-12 medium supplied with fetal bovine serum (10%).…”

Section: Methodsmentioning

confidence: 99%

“…The uptake of cabotegravir-glucuronide in singly-overexpressing OATP1B1, OATP1B3, OAT1, OAT3, and OAT4 cells was studied in the presence and absence of a prototypical inhibitor according to a previously published protocol (Patel et al, 2018). Briefly, confluent cell monolayers were washed twice with transport medium and preincubated with a prototypical inhibitor or DMSO at 37°C for 20 minutes.…”

Section: Cellular Uptakementioning

confidence: 99%

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Mechanistic Basis of Cabotegravir–Glucuronide Disposition in Humans

Patel

Eberl

Wolf

et al. 2019

J Pharmacol Exp Ther

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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 5 0.81) and MRP4 (Ft 5 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 5 0.66) and MRP4 (Ft 5 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.

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Section: Methodsmentioning

confidence: 99%

Section: Cellular Uptakementioning

confidence: 99%

Mechanistic Basis of Cabotegravir–Glucuronide Disposition in Humans

Patel

Eberl

Wolf

et al. 2019

J Pharmacol Exp Ther

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“…Quinone Atovaquone: Atovaquone is known to be predominantly cleared from the body through biliary excretion as the drug concentration in bile is ≥100-fold higher compared to that of the blood, and this is indicative of active biliary excretion. An in vitro study failed to demonstrate the involvement of OCTs and OATs in atovaquone liver uptake and excretion into bile 42 . Hence, co-administration of atovaquone with OCT substrates is not expected to result in any DDI.…”

Section: Mefloquinementioning

confidence: 99%

Pharmacokinetic Drug-Drug Interactions Mediated by Organic Cation Transporters: Are Antimalarial Drugs Significantly Affected?

ONYEJI

2024

Univ J Pharm Res

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A clear understanding of all the processes that influence drug disposition is important to enable a prediction of pharmacokinetic drug interactions. Xenobiotics are transported across bio-membranes and the process is mediated by various membrane transporters which include “Organic Cation Transporters” (OCTs). OCTs are specifically involved in the transport of several molecules that have positive charges in vivo and these include a wide variety of weakly basic drugs.As several antimalarial drugs are weakly basic and can be cationic in biological fluids, the contribution of OCTs to the drug disposition appears to be underestimated because most studies on the pharmacokinetic drug interaction with antimalarial drugs are focused on the interactions at the sites of drug metabolism. This review provides an update on the significance of OCTs on the pharmacokinetic disposition of antimalarial agents with a view to identifying potentials for drug interactions that could involve concurrently administered drugs which are either inhibitors or substrates of OCTs. A very significant likelihood exists for concurrent use of antimalarial drugs with other medicines because of the occurrence of comorbidities with malaria. There are limited studies on antimalarial pharmacokinetic drug-drug interaction studies in which role of OCTs are investigated. From the literature, and using in vitro studies, the following antimalarial drugs, chloroquine, piperaquine, proguanil, and cycloguanil have been reported to be substrates of different OCTs while tafenoquine, pyrimethamine, trimethoprim, quinine, and mefloquine were shown to be inhibitors. Atovaquone and artesunate were shown not to be substrates and did not demonstrate any inhibitory potency. This information provide basis for prediction of any potential interaction between antimalarial drugs and other co-administered medicines which are inhibitors/substrates of the transporter proteins. Peer Review History: Received 6 February 2024; Revised 15 March 2024; Accepted 26 April; Available online 15 May 2024 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr Average Peer review marks at initial stage: 6.5/10 Average Peer review marks at publication stage: 7.5/10 Reviewers: Dr. George Zhu, Tehran University of Medical Sciences, Tehran, Iran, sansan4240732@163.com Dr. Bilge Ahsen KARA, Ankara Gazi Mustafa Kemal Hospital, Turkey, ahsndkyc@gmail.com

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Hepatobiliary Disposition of Atovaquone: A Case of Mechanistically Unusual Biliary Clearance

Cited by 2 publications

References 20 publications

Mechanistic Basis of Cabotegravir–Glucuronide Disposition in Humans

Mechanistic Basis of Cabotegravir–Glucuronide Disposition in Humans

Pharmacokinetic Drug-Drug Interactions Mediated by Organic Cation Transporters: Are Antimalarial Drugs Significantly Affected?

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