Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat.
OBJECTIVE
The objective of this study was to evaluate the effect of a potent P-gp inhibitor, GF120918, on the systemic pharmacokinetics and antinociceptive pharmacodynamics of a single intravenous dose of morphine in rats.


METHODS
Male Sprague-Dawley rats received either 500 mg base/kg/d GF120918 or vehicle for 4 days by gavage, or no pretreatment. On day 4, morphine was administered as a 1- or 2-mg/kg i.v. bolus. Antinociception, expressed as percent of maximum possible response (%MPR), was evaluated over 300 min after morphine administration. Serial blood samples were collected and analyzed for morphine and morphine-3-glucuronide (M3G) by HPLC.


RESULTS
Morphine clearance and distribution volume were not altered significantly by GF120918. M3G AUC in the GF120918-treated rats was approximately 2-fold higher than in vehicle-treated rats. For both morphine doses, %MPR and the area under the effect-time curve at 300 min were significantly higher in the GF120918-treated rats. A pharmacokinetic/pharmacodynamic effect model accurately described the effect-concentration data for the rats that received 1-mg/kg morphine; ke0 was significantly smaller for GF120918- vs. vehicle-treated and control rats (0.060 +/- 0.028 vs. 0.228 +/- 0.101 vs. 0.274 +/- 0.026 min-1, p = 0.0023). EC50 and gamma were similar between treatment groups.


CONCLUSIONS
Pretreatment with GF120918 enhanced morphine antinociception, as assessed by the hot-lamp tail-flick assay, and elevated systemic M3G concentrations in rats. The differential pharmacologic response to morphine in the GF120918-treated animals could not be attributed to alterations in systemic morphine pharmacokinetics.
Letrent
S P
SP
School of Pharmacy, Division of Pharmaceutics, University of North Carolina at Chapel Hill 27599, USA.
Pollack
G M
GM
Brouwer
K R
KR
Brouwer
K L
KL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines / Q000494:pharmacology*; D000284:Administration, Oral; D000698:Analgesia; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D009022:Morphine Derivatives / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000701:Analgesics, Opioid; D007546:Isoquinolines; D009022:Morphine Derivatives; D044005:Tetrahydroisoquinolines; D009020:Morphine; C083501:Elacridar; C018108:morphine-3-glucuronide