title: Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study.
abstract: Thirty-three Collies (14 male and 19 female) were used in a dose-escalation study to determine the impact of ABCB1 genotype on loperamide pharmacokinetics (PK) and pharmacodynamics (PD). Loperamide was orally administered in four ascending doses (0.01, 0.05, 0.1, or 0.2 mg/kg) over a 4-wk period to fasted Collies. Comparisons were made within each dose to genotype, phenotype, and whether Collies received three (3D) or four (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration-versus-time profile estimated from time zero to the last quantifiable drug concentration, AUC0-last). In contrast, statistical differences in AUC0-last only occurred in the comparison between wild-type (WT) Collies versus homozygous mutant (Mut) Collies administered 0.1 mg/kg. Statistical differences in the proportionality relationship were observed when comparing 3D to 4D Collies, and the WT to Mut Collies. Intersubject variability in drug exposure tended to be twice as high between Mut and WT Collies. Associations were observed between systemic drug exposure and ataxia or depression but not between systemic drug exposure and mydriasis or salivation. Thus, Collies expressing the greatest sensitivity to CNS-associated effects of loperamide (Mut) tended to have higher drug exposure compared with those less sensitive to the adverse effects of loperamide. Genotype and phenotype only partially explained differences in loperamide PK and PD, suggesting this relationship may not be straightforward and that other factors need to be considered. Accordingly, the PD and PK of one P-glycoprotein substrate only partially predicted the likelihood of adverse responses to unrelated substrates.
authors.affiliation: Office of Research, Division of Applied Veterinary Research (M.J.M., H.F.Y.); Office of New Animal Drug Evaluation, Division of Scientific Support (J.Q) Office of New Animal Drug Evaluation (M.M.); Office of Research, Division of Residue Chemistry (H.L.); Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for Non-Food Animals (L.T., M.S.)-Center for Veterinary Medicine,US Food and Drug Administration, Silver Spring, Maryland michael.myers@fda.hhs.gov.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Myers
authors.affiliation: Office of Research, Division of Applied Veterinary Research (M.J.M., H.F.Y.); Office of New Animal Drug Evaluation, Division of Scientific Support (J.Q) Office of New Animal Drug Evaluation (M.M.); Office of Research, Division of Residue Chemistry (H.L.); Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for Non-Food Animals (L.T., M.S.)-Center for Veterinary Medicine,US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Office of Research, Division of Applied Veterinary Research (M.J.M., H.F.Y.); Office of New Animal Drug Evaluation, Division of Scientific Support (J.Q) Office of New Animal Drug Evaluation (M.M.); Office of Research, Division of Residue Chemistry (H.L.); Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for Non-Food Animals (L.T., M.S.)-Center for Veterinary Medicine,US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Office of Research, Division of Applied Veterinary Research (M.J.M., H.F.Y.); Office of New Animal Drug Evaluation, Division of Scientific Support (J.Q) Office of New Animal Drug Evaluation (M.M.); Office of Research, Division of Residue Chemistry (H.L.); Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for Non-Food Animals (L.T., M.S.)-Center for Veterinary Medicine,US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Junshan
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Office of Research, Division of Applied Veterinary Research (M.J.M., H.F.Y.); Office of New Animal Drug Evaluation, Division of Scientific Support (J.Q) Office of New Animal Drug Evaluation (M.M.); Office of Research, Division of Residue Chemistry (H.L.); Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for Non-Food Animals (L.T., M.S.)-Center for Veterinary Medicine,US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Troutman
authors.affiliation: Office of Research, Division of Applied Veterinary Research (M.J.M., H.F.Y.); Office of New Animal Drug Evaluation, Division of Scientific Support (J.Q) Office of New Animal Drug Evaluation (M.M.); Office of Research, Division of Residue Chemistry (H.L.); Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for Non-Food Animals (L.T., M.S.)-Center for Veterinary Medicine,US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Michele
authors.initials: M
authors.lastname: Sharkey
authors.affiliation: Office of Research, Division of Applied Veterinary Research (M.J.M., H.F.Y.); Office of New Animal Drug Evaluation, Division of Scientific Support (J.Q) Office of New Animal Drug Evaluation (M.M.); Office of Research, Division of Residue Chemistry (H.L.); Office of New Animal Drug Evaluation, Division of Therapeutic Drugs for Non-Food Animals (L.T., M.S.)-Center for Veterinary Medicine,US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Haile F
authors.initials: HF
authors.lastname: Yancy
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D000930:Antidiarrheals / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D008139:Loperamide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000930:Antidiarrheals; D008139:Loperamide