Prediction of pharmacokinetic clearance and potential Drug-Drug interactions for omeprazole in the horse using <i>in vitro</i> systems
Creators: name: Shibany, Khaled A.
name: Pratt, Stefanie L.
name: Aldurdunji, Mohammed
name: Totemeyer, Sabine
name: Paine, Stuart W.
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Medicine
subject: Molecular Biology
subject: Physiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: Inorganic Chemistry
subject: 60506 Virology

description: Horses are exposed to various kinds of medication, however, there are limited determinations of plasma clearance (CL<sub>p</sub>) for the drugs used due to the high cost of equine <i>in vivo</i> studies.Many of the CL<sub>p</sub> 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 (<i>n</i> = 3 horses).The V<sub>max</sub>, K<sub>m</sub> and intrinsic clearance (CL<sub>int</sub>) of omeprazole were determined via the substrate depletion method as well as K<sub>m</sub> values for the formation of three metabolites.The CL<sub>int</sub> values were extrapolated to <i>in vivo</i> hepatic plasma clearance (CL<sub>H</sub>) using the well stirred and parallel tube models.Cl<sub>p</sub> 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 K<sub>i</sub>, assuming competitive inhibition, was 15.4 ± 5 µM.To the authors’ knowledge, this is the first report showing the successful extrapolation of drug CL<sub>p</sub> in the horse using equine hepatocytes and the prediction of a DDI using microsomes. Horses are exposed to various kinds of medication, however, there are limited determinations of plasma clearance (CL<sub>p</sub>) for the drugs used due to the high cost of equine <i>in vivo</i> studies. Many of the CL<sub>p</sub> 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 (<i>n</i> = 3 horses). The V<sub>max</sub>, K<sub>m</sub> and intrinsic clearance (CL<sub>int</sub>) of omeprazole were determined via the substrate depletion method as well as K<sub>m</sub> values for the formation of three metabolites. The CL<sub>int</sub> values were extrapolated to <i>in vivo</i> hepatic plasma clearance (CL<sub>H</sub>) using the well stirred and parallel tube models. Cl<sub>p</sub> 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 K<sub>i</sub>, assuming competitive inhibition, was 15.4 ± 5 µM. To the authors’ knowledge, this is the first report showing the successful extrapolation of drug CL<sub>p</sub> in the horse using equine hepatocytes and the prediction of a DDI using microsomes.