Investigational New Drugs 14:147-151, 1996. 9 1996 KluwerAcademic Publishers. Printed in the Netherlands. Docetaxel serum protein binding with high affinity to alphal-acid glycoprotein Sail~ Urien ~, J6r6me Barr6 ~, Christophe Morin ~, Anne Paccaly 2, Guy Montay 2 and Jean-Paul Tillement ~ JLaboratoire de Pharmacologie, Facult~ de Mbdecine, Crdteil, France; 2Rh6ne Poulenc Rorer, Institut de Biopharmacie, Antony, France Key words: docetaxel, protein binding, plasma binding Summary The binding of docetaxel to human plasma proteins was studied by ultrafiltration at 37~ and pH 7.4. Docetaxel was extensively (> 98%) plasma protein bound. At clinically relevant concentrations (1-5 gg/ml), the plasma binding was concentration-independent. Lipoproteins, alphas-acid glycoprotein and albumin were the main carriers of docetaxel in plasma, and owing to the high interindividual variability of alpha I- acid glycoprotein plasma concentration, particularly in cancer, it was concluded that alphacacid glycoprotein should be the main determinant of docetaxel plasma binding variability. Drugs potentially coadministered with docetaxel (cisplatin, dexamethasone, doxorubicin, etoposide, vinblastine) did not modify the plasma binding of docetaxel. In blood, docetaxel was found to be mainly located in the plasma compartment (less than 15% associated to erythrocytes). Introduction Docetaxel (Taxotere | is a recent taxoid derivative prepared by semi-synthesis from the extract of the needles of Taxus Baccata. The pharmacological activity of docetaxel due to its interaction with the tubulin-microtubular system of the cell results in significant therapeutic activity against a variety of malignancies, including bronchial, breast and ovarian carcinomas (for a review, see [1]). The pharmacokinetics of docetaxel have been investigated in a series of Phase I studies [2] as well as in Phase II clinical trials where a sparse sampling strategy has been implemented to per- form a prospective population pharmacokinetic- pharmacodynamic evaluation [3]. This evaluation on 577 patients has shown that docetaxel clearance was related to body surface area, hepatic enzyme plasma level and particularly alphal-acid glyco- protein plasma concentration. Since alphas-acid glycoprotein is involved in plasma protein binding of numerous drugs [4], and drug plasma binding plays a role in drug disposition and drug effects [5], we have investigated in vitro the binding of docetaxel to serum proteins (including drug inter- actions) and erythrocytes. From these results, we have searched to predict the main determinant(s) for interindividual variation of docetaxel plasma binding by computer simulation. Materials and methods Chemicals. All chemicals were of analytical grade. Labelled 14C-docetaxel ditartrate (47 mCi/mmol or 1.73 GBq/mmol, Ref. CMM2035, batch 0392) was supplied by C.E.A. (Saclay, Gif-sur-Yvette 91191, France) and was 99.1% pure as checked by the manufacturer (CCM and HPLC). The drug was stored at -20~ under nitrogen until use. Cisplatin, dexamethasone, etoposide, vinblastine were pur- chased from Sigma, doxorubicin from Dakota Pharm. Human protein fractions and erythrocytes. Hu-