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.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Central Nervous System/metabolism , Ondansetron/pharmacokinetics , Serotonin 5-HT3 Receptor Antagonists/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/deficiency , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Animals , Brain/metabolism , Female , Male , Mice, Knockout , Models, Animal , Neuralgia/metabolism , Ondansetron/blood , Ondansetron/cerebrospinal fluid , Rats , Rats, Sprague-Dawley , Serotonin 5-HT3 Receptor Antagonists/blood , Serotonin 5-HT3 Receptor Antagonists/cerebrospinal fluid , Spinal Cord/metabolismABSTRACT
This study measured the concentrations of ondansetron in plasma and cerebrospinal fluid (CSF) in six volunteers after oral dosing to steady state. Ondansetron concentrations ranged from 39.5-147 ng ml-1 in plasma and from 2.6-15.4 ng ml-1 in CSF. There was good correlation between plasma and CSF concentrations (r = 0.89, p = 0.017). CSF concentrations were less than 15% of plasma concentrations in all cases, indicating that the rate of penetration of the blood brain barrier by ondansetron is low.
