Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine.
In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(-/-) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(-/-) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2- and 6-fold higher in mdr1a(-/-) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(-/-) mice. The cumulative fecal excretion (0-96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(-/-) mice. Biliary excretion was not significantly different in wt and mdr1a(-/-) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg/kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(-/-) mice. We conclude that P-glycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.
Sparreboom
A
A
Department of Clinical Chemistry, Antoni van Leeuwenhoek Huis, The Netherlands Cancer Institute, Amsterdam.
van Asperen
J
J
Mayer
U
U
Schinkel
A H
AH
Smit
J W
JW
Meijer
D K
DK
Borst
P
P
Nooijen
W J
WJ
Beijnen
J H
JH
van Tellingen
O
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000737:chemistry; D001682:Biological Availability; D018432:Drug Resistance, Multiple / Q000235:genetics; D005243:Feces / Q000737:chemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017239:Paclitaxel