Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine

Abstract

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 mg͞kg) 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 Pglycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

“…This study reports data on the in¯uence of PGP ablation on the intestinal handling of four compounds, paclitaxel, digoxin, etoposide and calcein, using isolated ileum from the mdr1a (7/7) mouse compared to tissues from FVB control animals expressing the mdr1a gene. The ®rst three of these compounds were chosen as prototypical PGP substrates for which there is clear evidence of both in vitro interaction with PGP and impaired bio-availability in in vivo systems (Schinkel et al, 1995;Cavet et al, 1996;Sparreboom et al, 1997;Makhey et al, 1998;Walle & Walle, 1998;Doppenschmitt et al, 1999;Fromm et al, 1999). The data presented here indicate that PGP plays an important role in de®ning the intestinal permeability of these compounds.…”

“…Both digoxin and paclitaxel have been reported to exhibit polarized e ux across epithelial cell monolayers consistent with interaction with xenobiotic transporters such as PGP (Fromm et al, 1999;Fromm, 2000;Sparreboom et al, 1997). Comparative studies across FVB control and mdr1a (7/7) mouse ileum were used to de®ne the degree to which PGP in¯uences the permeability of these compounds in intestinal tissues.…”

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

“…We studied 13 polymorphisms from six key paclitaxel elimination genes in 118 patients treated with paclitaxel, finding a statistically significant association for three cytochrome P450 functional genetic variants. The strategy followed was to select the most relevant polymorphisms, based on their functionality and allele frequency, in the genes essential for paclitaxel hepatic metabolism (CYP2C8, CYP3A4 and CYP3A5) 19,20 and transport (SLCO1B1, SLCO1B3 and ABCB1) [21][22][23][24] ( Figure 1) and assess their association with the paclitaxel dose that caused grade 2 neurotoxicity in our patients. Our data suggests a possible genetic predisposition to the occurrence of paclitaxelinduced neuropathy.…”

“…19,20 Concerning transport, paclitaxel uptake into the hepatocytes is mediated by the organic anion transporting polypeptide (OATP) 1B3 and, to some extent, (OATP) 1B1, 21,22 and efflux is mediated by P-glycoprotein. 23,24 The genes encoding these proteins are subjected to relevant genetic variation, which can alter drug metabolism and disposition, as we and others have shown. 17,[25][26][27] At present, despite its potential importance for neurotoxicity, very little is known about the genes responsible for the final concentration of paclitaxel and its metabolites in the nervous cells.…”

Penetration of Amitriptyline, but Not of Fluoxetine, into Brain is Enhanced in Mice with Blood-Brain Barrier Deficiency Due to Mdr1a P-Glycoprotein Gene Disruption

“…The first-mentioned assumption is supported by the findings that after subcutaneous injection of AMI, the plasma concentrations of AMI and its metabolites did not differ between mdr1ab Ϫ/Ϫ mice and FVB control mice (data not shown). A reduced elimination of a number of intravenously administered substrates of P-glycoprotein has been observed in P-glycoprotein Ϫ/Ϫ mutants (Mayer et al 1996;Borst and Schinkel 1997;Schinkel et al 1997;Sparreboom et al 1997).…”