Characterization of P‐glycoprotein inhibition at the blood brain barrier by ketoconazole and quinidine using the central pharmacodynamics of loperamide as an indicator of brain distribution

Background Loperamide (L) is a μ opioid agonist that does not cause central opiate effects, presumably due to P‐glycoprotein (Pgp) mediated efflux from the brain. L is a substrate for both CYP3A and Pgp. Ketoconazole (K) is a potent inhibitor of CYP3A. Quinidine (Q) and K inhibit Pgp. This study evaluated the ability of L to induce opioid effects in the presence of K or Q. Methods In a 2 part trial, 8 & 10 subjects were studied after the steady state K (400 mg QD) or single‐dose Q (100, 400, 800 mg) arms. L doses up to 16 mg were studied. Subjects received oral morphine (M) 30 mg as a positive control. Pupil diameter was measured via pupilometry. PK and PD parameters were determined using WinNonLin. Results PK and PD parameters (adjusted geometric means) for L 16 mg are noted in following Table: Conclusions The combination of L and K or Q produced modest central effects. While Q was somewhat more potent than K at inhibiting blood‐brain barrier (BBB) Pgp, the PD effect for both combinations was much less than M. These results suggest the clinical relevance of the interaction between L and either Q or K at the BBB is marginal. Clinical Pharmacology & Therapeutics (2005) 77 , P31–P31; doi: 10.1016/j.clpt.2004.12.011Rx K + P P + L Q100 + L Q400 + L Q800 + L K + L ML Cmax (μg/mL) — 3.10 4.04 * 5.58 * 7.78 * 16.0 * — L AUC (μg * h/mL) — 40.8 50.1 * 67.3 * 88.1 * 208 * — AUEC (mm * h) 3.2 6.7 11.8 14.4 + 7.31 10.6 + 25.2 +Emax (mm) 0.81 0.81 0.61 1.17 + 0.79 0.97 2.49 +* p< 0.01 vs P+ L; + p< 0.05 vs. P. PD effects for all Q doses and K+ L treatments were less than for M. (p< 0.01)