RT Journal Article
SR Electronic
T1 Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1392
OP 1407
DO 10.1124/dmd.115.063735
VO 43
IS 9
A1 Michael J. Myers
A1 Marilyn Martinez
A1 Hui Li
A1 Junshan Qiu
A1 Lisa Troutman
A1 Michele Sharkey
A1 Haile F. Yancy
YR 2015
UL http://dmd.aspetjournals.org/content/43/9/1392.abstract
AB 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.