The influence of enaminones on the transport and oral bioavailability of P-glycoprotein substrate therapeutic agents.
OBJECTIVE
The enaminones have shown high P-gp affinity and may act as P-gp modulators. This study investigated the potential inhibition of the enaminones on paclitaxel efflux in vitro compared to cyclosporin A, a known P-gp inhibitor, and the effectiveness of select enaminones on paclitaxel oral absorption in rats.


METHODS
Caco-2 transport of [14C]paclitaxel was evaluated in presence of various enaminones at 10(-5)M. Concentration-effect (10(-10)M to 10(-4)M) profiles for the enaminones, DM27 and/or DM40, with paclitaxel and cyclosporin A were determined. Male Sprague-Dawley (250-275 g) rats were orally administered either [14C]paclitaxel (30 microCi/kg) or [14C]paclitaxel/DM27 (7 mg/kg) and blood samples were collected. Paclitaxel brain concentrations were measured.


RESULTS
Papp(A-B) of [14C]paclitaxel, with DM27 and DM40 at 10(-5)M, was significantly (P < 0.05) higher versus control. DM27 produced a 360% and a 139% increase in Papp(A-B)Paclitaxel and Papp(A-B)Cyclosporin, respectively. DM40 displayed a 131% increase in Papp(A-B)Paclitaxel whereas cyclosporin A produced a 213% increase in Papp(A-B)Paclitaxel. Rats in the DM27 group displayed large Vdss/F values (23.35 liters/kg versus 14.62 liters/kg) and lower AUC (5.47 microg/ml min versus 8.74 microg/ml min) versus control. However, significantly higher levels (2.25-fold) of paclitaxel were observed in the brains of the DM27 group.


CONCLUSIONS
This study presents the enaminones as promising P-gp inhibitors with comparable potency to other P-gp inhibitors. Furthermore, the enaminones may improve conventional therapy when used in combination with P-gp substrate drugs.
Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, Rm 543, Baltimore, MD 21201, USA.
Noha N
NN
Salama
Kenneth R
KR
Scott
Natalie D
ND
Eddington
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D003512:Cyclohexanones; D016572:Cyclosporine; D017239:Paclitaxel