An in vitro examination of the impact of polyethylene glycol 400, Pluronic P85, and vitamin E d-alpha-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine.
The potential inhibitory effects of 3 excipients (polyethylene glycol [PEG] 400, Pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate [TPGS]) on the P-glycoprotein (P-gp) -mediated efflux of digoxin (DIG) and cytochrome P450 3A (CYP3A) -mediated metabolism of verapamil (VRP) have been examined in an in vitro permeability model. Experiments were conducted utilizing rat jejunal tissue mounted in diffusion chambers and included assessment of the serosal to mucosal (s to m) transport of DIG and the formation of norverapamil (NOR) during the mucosal to serosal transport of VRP, as measures of P-gp efflux and CYP3A metabolism, respectively. The presence of PEG at 1%, 5%, and 20% (wt/vol) reduced both the s to m flux of DIG (by 47%, 57%, and 64%, respectively, when compared to control) and the metabolism of VRP (by 54%, 78%, and 100%) in a concentration-dependent manner. P85 (0.1% wt/vol) significantly reduced s to m DIG flux by 47% and inhibited VRP metabolism by 42%. TPGS had insignificant effects on both metabolism and efflux at a concentration of 0.01% (wt/vol). The P-gp inhibitory effects of PEG and P85 were evident regardless of whether the excipient was added to the mucosal side, the serosal side, or both sides of the tissue. The current data suggest that inclusion of PEG and P85 as solubilizing agents during in vitro permeability assessment may have a significant impact on both drug metabolism and efflux processes. These compounds appear to exert their effects on P-gp primarily via direct transporter inhibition - or indirectly, through effects on buffer osmolarity, membrane fluidity, and/or mitochondrial toxicity and subsequent adenosine triphosphate (ATP) depletion.
Johnson
Brendan M
BM
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria, Australia.
Charman
William N
WN
Porter
Christopher J H
CJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D004077:Digoxin / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007422:Intestines / Q000166:cytology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D020442:Poloxamer / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000494:pharmacology; D013386:Succinates / Q000737:chemistry; D014700:Verapamil / Q000378:metabolism; D014810:Vitamin E / Q000737:chemistry / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012997:Solvents; D013386:Succinates; D020442:Poloxamer; D014810:Vitamin E; D011092:Polyethylene Glycols; D004077:Digoxin; D000255:Adenosine Triphosphate; D014700:Verapamil; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating