Probenecid interacts with the pharmacokinetics of morphine-6-glucuronide in humans.
BACKGROUND
Evidence obtained from porcine cell cultures and experiments in laboratory animals indicates that transmembrane transporters may play a role in the distribution of the active morphine metabolite morphine-6-glucuronide (M6G). This was evaluated in a study in healthy volunteers.


METHODS
Ten subjects received an intravenous M6G infusion for 30 min at a dosage of 0.5 mg/kg body weight, leading to M6G plasma concentrations approximately two to three times higher than those observed with analgesic morphine doses in subjects with normal kidney function. In a randomized, double-blind, three-way crossover fashion, subjects received 800 mg quinidine for inhibition of P-glycoprotein; 500 mg probenecid for inhibition of other transporters, including organic anion transporter peptide, multidrug resistance-related protein, and organic anion transporter families; or placebo 1 h before the start of M6G administration. Plasma concentrations of M6G and pupil size were measured for 7 h.


RESULTS
Probenecid pretreatment resulted in a decrease in the clearance of M6G from 8.3 +/- 1 l/h to 6.7 +/- 1.3 l/h (factor of 0.8; P < 0.05 vs. placebo cotreatment). This was paralleled by an increase by a factor of 1.2 of the area under the miotic effect-versus-time curves (P < 0.05 vs. placebo). In contrast, quinidine pretreatment had no influence on the pharmacokinetics of M6G.


CONCLUSIONS
The active morphine metabolite is subject to transmembrane transport by transporters inhibited by probenecid in humans.
Skarke
Carsten
C
Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Germany.
Langer
Michael
M
Jarrar
Marwan
M
Schmidt
Helmut
H
Geisslinger
Gerd
G
Lötsch
Jörn
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009022:Morphine Derivatives / Q000097:blood / Q000493:pharmacokinetics*; D011339:Probenecid / Q000494:pharmacology*; D011680:Pupil / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology; D012076:Renal Agents / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D026901:Membrane Transport Proteins; D009022:Morphine Derivatives; D012076:Renal Agents; C035349:morphine-6-glucuronide; D011802:Quinidine; D011339:Probenecid