Co-administration of cyclosporin enables oral therapy with paclitaxel

Abstract

Intravenous paclitaxel is associated with unpredictable side- effects largely due to the vehicle, Cremophor EL Oral paclitaxel, however, is poorly bioavailable due to its high affinity for the multidrug transporter P-glycoprotein (P-gp), abundantly present in the gastrointestinal tract 1 Borst P Schinkel AH Genetic dissociation of the function of mammalian P-glycoproteins. Trends Genet. 1997; 13: 217-222 Summary Full Text PDF PubMed Scopus (118) Google Scholar , 2 Schinkel AH Smit JJ van Tellingen O et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994; 77: 491-502 Summary Full Text PDF PubMed Scopus (2039) Google Scholar Studies in mdrla (−/−) knockout mice lacking P-gp revealed an increased oral uptake of paclitaxel 3 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 NatlAcad Sci. 1997; 4: 2031-2035 Crossref Scopus (837) Google Scholar We combined oral paclitaxel with the P-gp blocker SDZ PSC 833 or cyclosporin (Cs) in wild-type mice, resulting in a 10-fold increased systemic exposure to paclitaxel 4 van Asperen J van Tellingen O Sparreboom A et al. Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. BrJ Cancer. 1997; 76: 1181-1183 Crossref PubMed Scopus (194) Google Scholar To find out if co- administration of Cs might increase the absorption of oral paclitaxel, a proof-of-concept study was carried out in 14 patients with solid tumours Five patients received oral paclitaxel (intravenous formulation) at a dose of 60 mg/m 2 Schinkel AH Smit JJ van Tellingen O et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994; 77: 491-502 Summary Full Text PDF PubMed Scopus (2039) Google Scholar during the first course and intravenous paclitaxel at a dose of 175 mg/m 2 Schinkel AH Smit JJ van Tellingen O et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994; 77: 491-502 Summary Full Text PDF PubMed Scopus (2039) Google Scholar during subsequent courses Nine patients received one course of 60 mg/m 2 Schinkel AH Smit JJ van Tellingen O et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994; 77: 491-502 Summary Full Text PDF PubMed Scopus (2039) Google Scholar oral paclitaxel with 15 mg/kg Cs, and 175 mg/m 2 Schinkel AH Smit JJ van Tellingen O et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994; 77: 491-502 Summary Full Text PDF PubMed Scopus (2039) Google Scholar intravenous paclitaxel subsequently The first two courses were randomised in these patients and the pharmacokinetics of paclitaxel, Cs, Cremophor EL, and ethanol were determined. DEPARTMENT OF ERRORCo-administration of cyclosporin enables oral therapy with paclitaxel—In this Research Letter by Terwogt and colleagues (July 25, p 285) the penultimate sentence of the second paragraph should have read: “The highest detected plasma ethanol concentration was 0·01% (v/v)…”. Full-Text PDF