Manting Chiang1,2, Hyun-Moon Back1,2, Jong Bong Lee1, Sarah Oh1, Tiffany Guo1, Simone Girgis1, Celine Park1, Simon Haroutounian3, Leonid Kagan4,5. 1. Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA. 2. Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA. 3. Division of Clinical and Translational Research and Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA. 4. Department of Pharmaceutics, Ernest Mario, School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA. lkagan@pharmacy.rutgers.edu. 5. Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA. lkagan@pharmacy.rutgers.edu.
Abstract
PURPOSE: Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model. METHODS: Plasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose. RESULTS: Pgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39-5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision. CONCLUSIONS: The study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord.
PURPOSE: Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model. METHODS: Plasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose. RESULTS: Pgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39-5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision. CONCLUSIONS: The study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord.
Authors: Yumi Yamamoto; Pyry A Välitalo; Dirk-Jan van den Berg; Robin Hartman; Willem van den Brink; Yin Cheong Wong; Dymphy R Huntjens; Johannes H Proost; An Vermeulen; Walter Krauwinkel; Suruchi Bakshi; Vincent Aranzana-Climent; Sandrine Marchand; Claire Dahyot-Fizelier; William Couet; Meindert Danhof; Johan G C van Hasselt; Elizabeth C M de Lange Journal: Pharm Res Date: 2016-11-18 Impact factor: 4.200
Authors: Konstantinos Biliouris; Puneet Gaitonde; Wei Yin; Daniel A Norris; Yanfeng Wang; Scott Henry; Robert Fey; Ivan Nestorov; Stephan Schmidt; Mark Rogge; Lawrence J Lesko; Mirjam N Trame Journal: CPT Pharmacometrics Syst Pharmacol Date: 2018-08-16