Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine

Aims To investigate the effect of acute P-glycoprotein inhibition by the mu ltidrug-resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the phar macokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuron ide (M3G) and morphine-6-glucuronide (M6G). Methods In a double-blind, three-way crossover study, the pharmacokinetic a nd potentially adverse pharmacodynamic effects (reaction time, transcutaneo us PCO2, blood pressure) of morphine were compared with and without acute i nhibition of P-glycoprotein by PSC. The effects of PSC alone were also eval uated. The study was performed in 18 healthy male volunteers and pharmacody namic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With th e expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h. Results The infusion of PSC resulted in blood concentrations expected to in hibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant i ncrease in the AUC and C-max of M3G (11.8 and 8.3%, respectively). The t(1/ 2) and t(max) were unaffected. The pharmacokinetic parameters of PSC were n ot affected by coadministration with morphine. PSC did not significantly af fect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (E- max 48 ms, compared with the predose absolute reaction time of 644 ms), whi ch was not detected by the alertness-drowsiness score, indicating only slig ht sedation. There was a significant decrease in systolic blood pressure (E -min -9 mmHg), and a trend for a fall in diastolic blood pressure (E-min -1 4.5 mmHg) and respiratory rate (E-min -1.8 breath.min(-1)). For all these p arameters, the effects of PSC/morphine were similar to that of PSC alone, s uggesting some attenuation of morphine's effect. In contrast, morphine caus ed a significant increase in PCO2 (E-max 0.69 kPa) compared to PSC alone, i ndicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination. Conclusions Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic profile of morphine in a clinically significant manner.