Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel inpatients

The non-linear plasma pharmacokinetics of paclitaxel in patients has been w ell established, however, the exact underlying mechanism remains to be eluc idated. We have previously shown that the non-linear plasma pharmacokinetic s of paclitaxel in mice results from Cremophor EL. To investigate whether C remophor EL also plays a role in the non-linear pharmacokinetics of paclita xel in patients, we have established its pharmacokinetics in patients recei ving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokineti cs of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h s chedules was significantly lower than when using the longer 24- or 96-h inf usions (Cl175-3 h = 42.8 +/- 24.9 ml h(-1) m(-2); Cl175-24 h = 79.7 +/- 24. 3; P = 0.035 and Cl135-3 h = 44.1 +/- 21.8 ml h(-1) m(-1); Cl140-96 h = 211 .8 +/- 32.0; P < 0.001). Consequently the maximum plasma levels were much h igher (0.62%) in the 3-h infusions than when using longer infusion duration s. By using an in vitro equilibrium assay and determination in plasma ultra filtrate we have established that the fraction of unbound paclitaxel in pla sma is inversely related with the Cremophor EL level. Despite its relativel y low molecular weight. no Cremophor EL was found in the ultrafiltrate frac tion. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the app arent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable dist ribution and elimination kinetics and means that we must re-evaluate previo us assumptions on pharmacokinetics-pharmacodynamics relationships. (C) 1999 Cancer Research Campaign.