Enhanced Oral Bioavailability of Docetaxel by Coadministration of Cyclosporine: Quantitation and Role of P-Glycoprotein
Authors: Win L. Chiou, Ta Chen Wu, Chien Ma, Hyun Young Jeong, M.M. Malingré, J.H. Beijnen, J.H.M. Schellens
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.7.1951 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11919259 Enhanced Oral Bioavailability of Docetaxel by Coadministration of Cyclosporine: Quantitation and Role of P-Glycoprotein Win L. ChiouxWin L. ChiouSearch for articles by this author , Ta Chen WuxTa Chen WuSearch for articles by this author , Chien MaxChien MaSearch for articles by this author , Hyun Young JeongxHyun Young JeongSearch for articles by this author M.M. MalingréxM.M. MalingréSearch for articles by this author , J.H. BeijnenxJ.H. BeijnenSearch for articles by this author , J.H.M. SchellensxJ.H.M. SchellensSearch for articles by this author Show More University of Illinois at Chicago, Chicago, ILThe Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands https://doi.org/10.1200/JCO.2002.20.7.1951 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01042002In Reply:We appreciate the valuable remarks of Dr Chiou et al and the interest they took in our recent study.1 In summary, we demonstrated that by coadministration of cyclosporine, the systemic exposure to oral docetaxel (indicated as area under the plasma concentration-time curve [AUC]) increased 7.3-fold in comparison to oral drug ingestion without cyclosporine. Cyclosporine is an efficacious inhibitor of P-glycoprotein and cytochrome P450 (CYP) 3A4 in the gut wall and liver, which may explain our observations.1For the calculation of the bioavailability of docetaxel, coadministered with cyclosporine, the AUCoral (oral docetaxel + cyclosporine) was divided by the AUCiv (intravenous docetaxel), after dose correction. Chiou et al rightly point out that this procedure for estimation of the true bioavailability is only justified when the clearance of docetaxel is not influenced by cyclosporine. This is not plausible, however, as explained by Chiou et al and substantiated by our recent observations in mice.2 These laboratory studies clearly demonstrate that cyclosporine decreases the clearance of docetaxel. The bioavailability issue stipulated by Chiou et al could have been overcome by measuring docetaxel AUCs in patients given intravenous docetaxel and cyclosporine. We followed this strategy in mice to investigate the oral bioavailability of paclitaxel coadministered with cyclosporine.3 However, patient data were not available for the calculation of the true bioavailability with the total clearance of docetaxel in combination with cyclosporine. The term “apparent” oral bioavailability, therefore, is more applicable, as we have previously defined, also in our studies on the enhancement of paclitaxel bioavailability by coadministration with cyclosporine.2,4 For paclitaxel, the issue is even more complicated because the pharmaceutical vehicle Cremophor EL also decreases substantially the clearance of the drug while this excipient is not entering the systemic circulation after oral administration.4-6In our patients, we could not detect docetaxel metabolites in plasma after oral administration of the drug alone. With cyclosporine, however, significant amounts of four metabolites could be measured. This paralleled with low and high docetaxel levels in plasma. In an earlier study with patients treated with intravenous docetaxel, we could only measure metabolites shortly after the end of the 1-hour infusion in those individuals with high docetaxel levels (low drug clearance) due to impaired hepatic liver function.7 This could mean that CYP is involved in the clearance of the metabolites. On the other hand, there are no experimental data to support the hypothesis that the potential CYP- and/or P-glycoprotein (other transporters?)–mediated clearance of the metabolites is influenced by cyclosporine.We agree with Chiou et al that P-glycoprotein may also affect the clearance of docetaxel, although the effects of CYP also seem to be very prominent.2 In wild-type mice receiving oral docetaxel (without cyclosporine), we recovered 38% unchanged drug (+ 33% metabolites) in feces; for paclitaxel, 80% to 90% of unchanged drug was found.2 This indicates both substantial absorption and metabolism of docetaxel in wild-type, P-glycoprotein–proficient mice after oral administration without cyclosporine. More data will be published soon.1. Malingré MM, Richel DJ, Beijnen JH, et al: Coadministration of cyclosporin strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 19:: 1160,2001-1166, Link, Google Scholar2. Bardelmeijer H, Ouwehand M, Schellens JHM, et al: The effects of cyclosporin A on the oral bioavailability of docetaxel in mice. Proc Am Assoc Cancer Res 42:: 951,,2001 (abstr) Google Scholar3. van Asperen J, van Tellingen O, van der Valk MA, et al: Enhanced oral absorption and decreased elimination of paclitaxel in mice co-treated with cyclosporin A. Clin Cancer Res 4:: 2293,1998-2299, Medline, Google Scholar4. Meerum Terwogt JM, Malingré MM, Beijnen JH, et al: Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5:: 3379,1999-3384, Medline, Google Scholar5. Sparreboom A, van Tellingen O, Nooijen WJ, et al: Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res 56:: 2112,1996-2115, Medline, Google Scholar6. Malingré MM, Schellens JHM, van Tellingen O, et al: The co-solvent Cremophor EL limits the absorption of orally administered paclitaxel in cancer patients. Br J Cancer 85:: 1472,2001-1477, Crossref, Medline, Google Scholar7. Rosing H, Lustig V, van Warmerdam LJC, et al: Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion. Cancer Chemother Pharmacol 45:: 213,2000-218, Crossref, Medline, Google Scholar