Studies on the pharmacokinetics of chlorambucl and prednimustine in patients using a new high-performance liquid chromatographic assay

Abstract

Following the oral administration of either chlorambucil/prednisolone or prednimustine to patients, the plasma levels of free chlorambucil and phenylacetic acid mustard, the beta-oxidation product of chlorambucil, were measured using a new high-performance liquid chromatographic (HPLC) assay. This assay permitted the simultaneous detection of the analyzed compounds with a lower limit of detection of 30 ng/ml. The pharmacokinetics of chlorambucil and phenylacetic acid mustard were found to be entirely different when prednimustine was administered as opposed to its components chlorambucil and prednisolone together. After the ingestion of the conjugate, the plasma concentration-time curves of chlorambucil and phenylacetic acid mustard showed a "delayed" pattern compared with those obtained after the administration of the components. The mean area under the concentration-time curves (AUCs) of prednimustine-derived chlorambucil and phenylacetic acid mustard were 25% and 40%, respectively, of the areas obtained after a stoichiometrically equivalent dose of chlorambucil. Free plasma prednimustine could not be detected at any time. This different pharmacokinetic behavior might offer an explanation for the superior therapeutic effects of prednimustine demonstrated by clinical studies.

Pharmacokinetics of Chlorambucil in Patients with Chronic Lymphocytic Leukaemia: Comparison of Different Days, Cycles and Doses

“…Probably due to a longer half-life of terminal elimination, approximated plasma clearance of chlorambucil in our study was less than those reported in the literature: 1.8 versus 2.6 ml/min./kg (Oppitz et al 1989;Benet et al 1996). The observation that AUC¬ was reduced only in those patients with a relatively high AUC at start suggests saturable induction of those enzymes involved in chlorambucil metabolism.…”

“…Chlorambucil and phenylacetic acid mustard plasma concentrations were measured using an isocratic reversed-phase HPLC method modified from previous protocols (Zakaria & Brown 1982;Adair et al 1985;Oppitz et al 1989). The HPLC equipment consisted of a Varian 5000 pump, a UV-detector (Varian UV-100, 254 nm) and a Shimadzu C-R5A integrator.…”

“…The mean arrival time (MATΩLag timeπ1/t 1/2 abs) and mean residence time (MRTΩAUMC/AUC) were approximated (Cheng & Jusko 1988;Veng-Pedersen 1989) using the program MOM (Efthymiopoulos et al 1989). The steady-state distribution volume (V d ) was estimated using the first moment AUC (AUMC) and AUC¬, and assuming an oral bioavailability of 90% for chlorambucil (Farmer 1987;Oppitz et al 1989;Jack 1992). Apparent plasma clearance was approximated using Vdist, a and b (Jusko 1986).…”

“…In the fasting state, oral bioavailability is between 70% and 90% (Newell et al 1983;Oppitz et al 1989;Jack 1992), but food decreases it significantly . Chlorambucil is almost entirely metabolized, primarily in the liver by a microsomal enzyme system (McLean et al 1976;Farmer 1987;Dollery 1999).…”

Comparative Pharmacokinetics of Chlorambucil and Prednimustine after Oral Administration

“…While the bio availability of chlorambucil and prednisolone is more than 70% [7. 25, 32], previous studies found that the availability of these compounds from prednimustine ranged from 20 to 50% [5,28,32,33,35].…”