Doxorubicin and doxorubicinol: intra-and inter-individual variations of pharmacokinetic parameters

Abstract

Doxorubicin was given by short i.v. infusion (dose range 25-72 mg/m2) to 18 patients who underwent three to seven successive courses of chemotherapy (total, 57 courses). Plasma levels of doxorubicin and its major metabolite doxorubicinol were determined by high-performance liquid chromatography over a 48-h period after the infusion. Pharmacokinetic parameters for the parent drug and its metabolite were calculated for each course of treatment. The results show considerable inter- and intraindividual variations for most parameters. The coefficients of variation (CV) ranged from 37% to 93% (inter-individual) and from 6% to 59% (intra-individual). Nevertheless, we observed a good stability over successive courses for terminal half-life in six patients (CV, 6%-25%) and for clearance and AUC in four subjects (CV, 10%-22%). The ratio of the AUCs for doxorubicinol: doxorubicin averaged 0.514. The pharmacokinetic pattern of doxorubicinol was biphasic in plasma of the majority of patients. We propose a model for curve-fitting of these metabolite plasma concentrations that is based on two successive releases of the compound in the plasma compartment, separated by a lag time.

NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity

“…44 The lower incidence of heart damage after doxorubicin infusion as opposed to bolus injection suggests a role for peak levels of the drug in doxorubicin-induced cardiotoxicity. 45 Significant interindividual differences in doxorubicin pharmacokinetics have been reported previously, 46,47 and they could result from genetic variants in transporters such as MRP2. The 2 missense variants associating with ACT, Val1188Glu (rs8187694), and Cys1515Tyr (rs8187710), were initially described in the Japanese.…”

Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database

“…After administration, doxorubicin is partially converted into several metabolites with doxorubicinol being the major metabolite [6,8,9]. Like almost all anti-tumour agents, the pharmacokinetics of doxorubicin and its metabolites vary widely between patients with inter-individual coefficients of variation for area under the curve, volume of distribution, and clearance being in the range of 60-90% [6,8].…”

“…Like almost all anti-tumour agents, the pharmacokinetics of doxorubicin and its metabolites vary widely between patients with inter-individual coefficients of variation for area under the curve, volume of distribution, and clearance being in the range of 60-90% [6,8]. Several mechanisms may underlie this inter-individual variation including differences in hepatic function [6], gender, BMI [5] and genetic variants in genes encoding products involved in the metabolism of doxorubicin [10].…”

Genotyping the risk of anthracycline-induced cardiotoxicity

“…The observed association could be caused by a reduced biliary elimination of doxorubicin, which normally accounts for 50% of its disposition [33]. Significant inter-individual differences in doxorubicin pharmacokinetics have been previously reported [34,35] and they could result from genetic variants in transporters, such as MRP2.…”