@article {Myersdmd.115.063735, author = {Michael J Myers and Marilyn Martinez and Hui Li and Junshan Qiu and Lisa Troutman and Michele Sharkey and Haile F. Yancy}, title = {Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study}, elocation-id = {dmd.115.063735}, year = {2015}, doi = {10.1124/dmd.115.063735}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Thirty three Collies (17 male and 16 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, 0.1or 0.2 mg/kg) over a four week period to fasted Collies. Each Collie{\textquoteright}s ABCB1 genotype and ivermectin (IVM) sensitivity (phenotype) was known prior to study enrollment. Depending upon the resulting magnitude of its adverse reaction (ataxia and depression), animals were either discontinued from further dosing after receiving only 3 of the 4 doses (i.e., maximum dose received = 0.1 mg/kg) or after receiving all four doses (maximum dose = 0.2 mg/kg). Within each dose level, comparisons were made with respect to genotype, phenotype, and whether the Collies received 3 (3D) or 4 (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration vs time profile estimated from time zero to the last quantifiable drug concentration, AUC0-last). In contrast, statistically significant differences in AUC0-last only occurred in the comparison between wild-type (WT) Collies versus the homozygous mutant Collies administered 0.1 mg/kg. Statistically significant differences in the proportionality relationship were observed when comparing the 3D and 4D Collies, the WT and homozygous mutant (mu/mu) Collies. The intersubject variability in drug exposure tended to be nearly twice as high between the Collies homozygous for this mutation (mu/mu) compared to that seen between the 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 the CNS-associated effects of loperamide (homozygous mutant) tended to have higher drug exposure as compared to those that were less sensitive to the adverse effects of loperamide. However, genotype and phenotype only partially explained differences in PK and PD, suggesting that this relationship may not be straightforward and that other factors impacting loperamide PK and PD need to be considered. Accordingly, the PD and PK of one P-gp substrate only partially predicted the likelihood of adverse responses to unrelated substrates.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2015/07/07/dmd.115.063735}, eprint = {https://dmd.aspetjournals.org/content/early/2015/07/07/dmd.115.063735.full.pdf}, journal = {Drug Metabolism and Disposition} }