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© 2002 American Society for Clinical Oncology
Enhanced Oral Bioavailability of Docetaxel by Coadministration of Cyclosporine: Quantitation and Role of P-GlycoproteinUniversity of Illinois at Chicago, Chicago, IL To the Editor:In the February 15, 2001, issue of the Journal of Clinical Oncology, Malingré et al1 published an interesting and useful study on the enhancement of absorption and absolute bioavailability of oral docetaxel by oral coadministration of cyclosporine. They reported that the mean (± SD) total area under the plasma concentration-time curve (AUC) in patients receiving only (control) oral docetaxel 75 mg/m2 was 0.37 ± 0.33 mg·h/L, whereas that in patients also dosed with oral cyclosporine was 2.71 ± 1.81 mg·h/L. They further reported that the absolute bioavailability of oral docetaxel was 8% ± 6% without and 90% ± 44% with cyclosporine. Absolute bioavailability (F) is conventionally defined as the fraction or percentage of oral dose available to the general blood circulation and is calculated by the following equation in linear kinetics:2,3
where CL is the total clearance of drug in the body. A review of their article revealed that their calculation of the absolute bioavailability of docetaxel in the control study without cyclosporine was correctly determined because the CL was determined after intravenous administration without cyclosporine. The authors used the same CL value to determine absolute bioavailability of docetaxel when cyclosporine was coadministered in the interaction study, apparently assuming no change in the CL of docetaxel by cyclosporine. However, such a critical assumption is inconsistent with reports that cyclosporine, a cytochrome P450 3A inhibitor, may also decrease CL for other cytochrome P450 3A substrates. For example, oral administration of cyclosporine 50 mg/kg has been reported to decrease the CL of intravenous paclitaxel by approximately 70% (from 0.92 ± 0.07 to 0.28 ± 0.01 L/h/kg) in mice.4 Therefore, it seems likely that docetaxel’s mean absolute bioavailability of 90% reported by Malingré et al in their interaction study may be considerably overestimated. This overestimation of oral bioavailability may also have occurred with their earlier study5 on the effect of coadministration of oral cyclosporine on the absolute bioavailability of paclitaxel in patients, because the new CL during the interaction study was not obtained and only the same CL obtained during the control study was used to calculate absolute bioavailability. In that study, an eight-fold higher absolute bioavailability value of paclitaxel was reported because of cyclosporine coadministration.5 Malingré et al1 also found significant amounts of four metabolites of docetaxel in plasma after coadministration with cyclosporine. These metabolites, interestingly, were not detected in plasma after oral administration of the drug alone. They stated that such increased metabolism after coadministration with cyclosporine may result in lower levels of the active drug and, possibly, reduced efficacy. They further stated that the achieved gain in increased uptake largely outweighs the possible loss by the increased metabolism.1 We wish to point out that increased metabolism per se may not necessarily result in lower levels of the parent drug, even if one assumes no change in uptake. In addition to oral bioavailability, plasma levels and AUCoral are determined by CL. The above-mentioned lower CL of docetaxel with coadministration of cyclosporine is theoretically expected to increase its plasma levels and AUCoral. In addition to the above-mentioned direct inhibition of the enzymatic activity by cyclosporine, P-glycoprotein may also play an important role in affecting the CL of docetaxel. For example, compared with wild-type mice, the CL of erythromycin6-8 and paclitaxel9 was markedly reduced and their plasma drug levels were markedly increased in P-glycoprotein knockout mice after intravenous administration, despite their higher metabolite levels (ie, increased metabolism) and their virtually identical hepatic enzyme contents. The decrease in the metabolic clearance of erythromycin and paclitaxel has been attributed mainly to the indirect inhibition of metabolism of parent drug due to accumulation of metabolites, also assumed to be P-glycoprotein substrates, in hepatocytes and enterocytes.7,8,10,11 For tacrolimus, which is metabolized almost exclusively in the body, hepatic metabolic clearance and apparent hepatic intrinsic clearance have been estimated to be reduced by 65% and 90%, respectively, in the P-glycoprotein knockout mice compared with wild-type mice, apparently due to the same mechanism.10 It is possible that cyclosporine, a potent P-glycoprotein inhibitor, may also significantly decrease the hepatic and intestinal metabolic clearance of docetaxel by the same P-glycoprotein–mediated mechanism. It is hoped that the above discussions may be of interest to your readers and may stimulate further research in this rapidly evolving area. REFERENCES
1.
Malingré MM, Richel DJ, Beijnen JH, et al: Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 19: 1160-1166, 2001 2. Lee MG, Chiou WL: Studies on potential factors affecting incomplete absorption of furosemide: Gastric first-pass effect. J Pharmacokinet Biopharm 11: 623-640, 1983[CrossRef][Medline] 3. Chiou WL: The rate and extent of oral bioavailability versus the rate and extent of oral absorption: Clarification and recommendation of terminology. J Pharmacokinet Biopharm 28: 3-6, 2001[CrossRef][Medline]
4.
Van Asperen J, Van Tellingen O, Van der Valk MA, et al: Enhanced oral absorption and decreased elimination of paclitaxel in mice cotreated with cyclosporin A. Clin Cancer Res 4: 2293-2297, 1998
5.
Meerum Terwogt JM, Malingré MM, Beijnen JH, et al: Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5: 3379-3384, 1999
6.
Lan LB, Dalton JT, Schuetz EG: Mdr1 limits CYP3A metabolism in vivo. Mol Pharmacol 58: 863-869, 2000 7. Chiou WL, Jeong HY, Wu TC, et al: Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization. Clin Pharmacol Ther 70: 305-310, 2001[CrossRef][Medline] 8. Chiou WL, Jeong HY, Wu TC, et al: Erythromycin breath test. Clin Pharmacol Ther 70: 397-399, 2001
9.
Sparreboom A, Van Asperen J, Mayer U, et al: Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 94: 2031-2035, 1997 10. Chiou WL, Chung SM, Wu TC: Apparent lack of effect of P-glycoprotein on the gastrointestinal absorption of a substrate, tacrolimus, in normal mice. Pharm Res 17: 205-208, 2000[CrossRef][Medline] 11. Chiou WL, Chung SM, Wu TC: Potential role of P-glycoprotein in affecting hepatic metabolism of drugs. Pharm Res 17: 903-905, 2000[CrossRef][Medline]
ResponseThe Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands In 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.1 For 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.4-6 In 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. REFERENCES 1. Malingré MM, Richel DJ, Beijnen JH, et al: Coadministration of cyclosporin strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 19: 1160-1166, 2001 2. 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) 3. 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: 2293-2299, 1998 4. Meerum Terwogt JM, Malingré MM, Beijnen JH, et al: Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5: 3379-3384, 1999
5.
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: 2112-2115, 1996 6. 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: 1472-1477, 2001[CrossRef][Medline] 7. 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: 213-218, 2000[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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