Prediction of Pharmacokinetic Clearance and Potential Drug-Drug Interactions for Omeprazole in the Horse using in vitro Systems

Shibany, Khaled A.; Pratt, Stephanie L.; Aldurdunji, Mohammed; Totemeyer, Sabine; Paine, Stuart W

Abstract

Horses are exposed to various kinds of medication, however, there are limited determinations of plasma clearance (CLp) for the drugs used due to the high cost of equine in vivo studies. Many of the CLp values generated come from the equine sports industry for determining drug plasma screening limits in the control of medications at the time of competition.

The kinetics of omeprazole metabolism were investigated in freshly isolated and cryopreserved equine hepatocytes and hepatic microsomes (n = 3 horses). The Vmax, Km and intrinsic clearance (CLint) of omeprazole were determined via the substrate depletion method as well as Km values for the formation of three metabolites. The CLint values were extrapolated to in vivo hepatic plasma clearance (CLH) using the well stirred and parallel tube models.

Clp for omeprazole was successfully predicted using freshly isolated or cryopreserved equine hepatocytes, while microsomes under-predicted. Equine microsomes were used to perform a drug-drug interaction (DDI) study between omeprazole and chloramphenicol. The average inhibitor constant Ki, assuming competitive inhibition, was 15.4 ± 5 µM.

To the authors’ knowledge, this is the first report showing the successful extrapolation of drug CLp in the horse using equine hepatocytes and the prediction of a DDI using microsomes.

Citation

Shibany, K. A., Pratt, S. L., Aldurdunji, M., Totemeyer, S., & Paine, S. W. (2020). Prediction of Pharmacokinetic Clearance and Potential Drug-Drug Interactions for Omeprazole in the Horse using in vitro Systems. Xenobiotica, 50(10), 1220-1227. https://doi.org/10.1080/00498254.2020.1764131

• Journal Article Type: Article
• Acceptance Date: Apr 29, 2020
• Online Publication Date: May 20, 2020
• Publication Date: 2020
• Deposit Date: Apr 30, 2020
• Publicly Available Date: May 21, 2021
• Journal: Xenobiotica
• Print ISSN: 0049-8254
• Electronic ISSN: 1366-5928
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 50
• Issue: 10
• Pages: 1220-1227
• DOI: https://doi.org/10.1080/00498254.2020.1764131
• Keywords: Toxicology; Biochemistry; Health, Toxicology and Mutagenesis; Pharmacology; General Medicine; Equine, in vitro in vivo extrapolation, Omeprazole, Equine hepatocytes, Liver microsomes
• Public URL: https://nottingham-repository.worktribe.com/output/4365629
• Publisher URL: https://www.tandfonline.com/doi/abs/10.1080/00498254.2020.1764131?journalCode=ixen20
• Additional Information: This is an Accepted Manuscript of an article published by Taylor & Francis in Xenobiotica on 20/05/2020, available online: http://www.tandfonline.com/10.1080/00498254.2020.1764131