Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study

Abstract

The pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30-35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, less than or equal to 60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2-12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was less than 60 ml/min [group N, 122.8 +/- 44.0 l/h; group L, 104.4 +/- 27.7 l/h (P = 0.58) vs group R, 83.4 +/- 18.3 l/h (P = 0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6 +/- 10.8 h; group L, 69.9 +/- 10.2 h (P = 0.27) vs group R, 83.2 +/- 10.9 h (P = 0.025) and t1/2 gamma: group N, 41.3 +/- 10.1 h; group L, 47.0 +/- 7.4 h (P = 0.31) vs group R, 55.8 +/- 8.2 h (P = 0.025)]. After oral treatment, drug absorption occurred during in the first 2-4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4-18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1-21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of Experimental Kidney Disease on the Functional Expression of Hepatic Reductases

“…For instance, bupropion exposure is dramatically increased by 126% in patients with impaired kidney function, suggesting reduced metabolic clearance (Turpeinen et al, 2007). Moreover, a 30% decrease in the metabolic clearance of idarubicin was reported in patients with creatinine clearance of ,60 ml/min (Camaggi et al, 1992). This suggests that phase I reduction of drugs may be affected by kidney disease.…”

“…Collectively, reductase enzymes play key roles in the biotransformation of diverse endogenous compounds such as bile acids, glucocorticoids, and prostaglandins, and numerous drugs Matsunaga et al, 2006;Oppermann, 2007;Malatkova and Wsol, 2014). Although the pharmacokinetics of several drugs that are reductase substrates, including idarubicin (Camaggi et al, 1992) and bupropion (Turpeinen et al, 2007), are altered in patients with CKD, the effect of impaired kidney function on specific hepatic reductase enzymes has not been assessed to date.…”

Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary

“…Using a slightly different definition of mild-to-moderate liver dysfunction (AST 1.5-4ϫ ULN, ALT 1.5-8ϫ ULN, and ALP 1.5-2ϫ ULN), Camaggi et al [12] found no significant PK alterations. While the authors concluded that no dose reductions were required in the presence of mild-to-moderate hepatic impairment, the data were insufficient to make recommendations for patients with severe hepatic impairment.…”

Pharmacokinetics and toxicity of idarubicin in the rat

“…IDA is metabolised in the liver and other tissues to its major metabolite, IDOL, which has been shown to be as active as IDA [2]. IDA also has the advantage of being available for oral administration [3,4]. In addition, IDA and IDOL are less affected by topoisomerase II-related multidrug resistance than daunorubicin [5].…”