Meerum Terwogt J M, Malingré M M, Beijnen J H, ten Bokkel Huinink W W, Rosing H, Koopman F J, van Tellingen O, Swart M, Schellens J H
Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Clin Cancer Res. 1999 Nov;5(11):3379-84.
i.v. paclitaxel is inconvenient and associated with significant and poorly predictable side effects largely due to the pharmaceutical vehicle Cremophor EL. Oral administration may be attractive because it may circumvent the use of Cremophor EL. However, paclitaxel, as well as many other commonly applied drugs, has poor bioavailability caused by high affinity for the mdrl P-glycoprotein drug efflux pump, which is abundantly present in the gastrointestinal tract. Consequently, inhibition of P-glycoprotein by oral cyclosporin A (CsA) should increase systemic exposure of oral paclitaxel to therapeutic levels. A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral paclitaxel of 60 mg/m2 with or without 15 mg/kg CsA and with i.v. paclitaxel in subsequent courses. The pharmacokinetics of paclitaxel and its major metabolites were determined during the first two courses. In addition, levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral paclitaxel in combination with CsA was 8-fold higher than after oral paclitaxel alone (P<0.001). Therapeutic concentrations were achieved on average during 7.4 h, which is comparable with an equivalent i.v. dose. The oral combination was well tolerated and did not induce gastrointestinal toxicity or myelosuppression. Cremophor EL plasma levels after oral drug administration were undetectable. In conclusion, coadministration of oral CsA increased the systemic exposure of oral paclitaxel from negligible to therapeutic levels. The combination enables treatment with oral paclitaxel. Undetectable Cremophor EL levels after oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel.
静脉注射紫杉醇不方便，且与严重且难以预测的副作用相关，这主要归因于药物载体聚氧乙烯蓖麻油（Cremophor EL）。口服给药可能具有吸引力，因为它可以避免使用聚氧乙烯蓖麻油。然而，紫杉醇以及许多其他常用药物，由于对多药耐药蛋白1（mdrl）P-糖蛋白药物外排泵具有高亲和力，导致生物利用度较差，而该泵在胃肠道中大量存在。因此，口服环孢素A（CsA）抑制P-糖蛋白应可使口服紫杉醇的全身暴露增加至治疗水平。在14例实体瘤患者中进行了一项概念验证研究。患者接受一个疗程的60mg/m²口服紫杉醇，加或不加15mg/kg CsA，并在随后的疗程中接受静脉注射紫杉醇。在前两个疗程中测定了紫杉醇及其主要代谢物的药代动力学。此外，还测量了CsA、聚氧乙烯蓖麻油和乙醇的水平。口服紫杉醇联合CsA的生物利用度比单独口服紫杉醇高8倍（P<0.001）。平均在7.4小时内达到治疗浓度，这与等效静脉注射剂量相当。口服联合用药耐受性良好，未引起胃肠道毒性或骨髓抑制。口服给药后聚氧乙烯蓖麻油血浆水平检测不到。总之，口服CsA可使口服紫杉醇的全身暴露从可忽略不计增加至治疗水平。这种联合用药使得口服紫杉醇治疗成为可能。口服给药后聚氧乙烯蓖麻油水平检测不到可能对口服紫杉醇治疗的安全性产生非常有益的影响。
