Role of P‐glycoprotein in the intestinal absorption and clinical effects of morphine

There is considerable and unexplained individual variability in the morphine dose‐effect relationship. The efflux pump P‐glycoprotein regulates brain access and intestinal absorption of numerous drugs. Morphine is a P‐glycoprotein substrate in vitro, and P‐glycoprotein affects morphine brain access and pharmacodynamics in animals. However, the role of P‐glycoprotein in human morphine disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous morphine are greater after inhibition of intestinal and brain P‐glycoprotein, with the P‐glycoprotein inhibitor quinidine used as an in vivo probe. Methods Two randomized, double‐blind, placebo‐controlled, balanced crossover studies were conducted in normal healthy volunteers after institutional review board–approved informed consent was obtained. In the first protocol, pupil diameter was evaluated after intravenous morphine administration (0.15 mg/kg), 1 hour afteroral quinidine or placebo. In the second protocol, plasma morphine and glucuronide metabolite concentrations and pupil diameters were evaluated after oral morphine administration (30 mg), dosed 1 hour after oral quinidine (600 mg) or placebo. Results Quinidine had no effect on intravenous morphine effects (time to maximum miosis, maximumeffect, or area under the curve [AUC] of miosis versus time). Quinidine increased the oral morphine maximum plasma concentration (31.8 ± 14.9 ng/mL versus 16.9 ± 7.4 ng/mL, P < .05) and AUC (65.1 ± 21.5 versus 40.8 ng · h · mL −1 ± 14 ng · h · mL −1 , P < .05) but had no effect on elimination rate. Plasma morphine glucuronide concentrations were unchanged; however, the morphine glucuronide/morphine ratios were diminished by quinidine. Differences in oral morphine miosis (AUC, 16.8 ± 9.3 mm · h versus 10.8 ± 6.5 mm · h; P < .05) were commensurate with changes in plasma morphine concentration, and concentration‐effect relationships were unchanged. Quinidine altered subjective self‐assessments of oral but not intravenous morphine effects. Discussion Quinidine increased the absorption and plasma concentrations of oral morphine, suggesting that intestinal P‐glycoprotein affected the absorption, bioavailability, and, hence, clinical effects of oral morphine. However, quinidine had no effect on morphine concentration‐effect relationships, suggesting that if quinidine is an effective inhibitor of brain P‐glycoprotein then P‐glycoprotein did not appear to have a significant effecton brain access of morphine. Clinical Pharmacology & Therapeutics (2003) 74 , 543–554; doi: 10.1016/j.clpt.2003.08.011