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Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study. 1992

C M Camaggi, and E Strocchi, and P Carisi, and A Martoni, and A Tononi, and M Guaraldi, and M Strolin-Benedetti, and C Efthymiopoulos, and F Pannuti
Department of Organic Chemistry, University of Bologna, Italy.

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)

UI MeSH Term Description Entries
D007262 Infusions, Intravenous The long-term (minutes to hours) administration of a fluid into the vein through venipuncture, either by letting the fluid flow by gravity or by pumping it. Drip Infusions,Intravenous Drip,Intravenous Infusions,Drip Infusion,Drip, Intravenous,Infusion, Drip,Infusion, Intravenous,Infusions, Drip,Intravenous Infusion
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D007674 Kidney Diseases Pathological processes of the KIDNEY or its component tissues. Disease, Kidney,Diseases, Kidney,Kidney Disease
D008113 Liver Neoplasms Tumors or cancer of the LIVER. Cancer of Liver,Hepatic Cancer,Liver Cancer,Cancer of the Liver,Cancer, Hepatocellular,Hepatic Neoplasms,Hepatocellular Cancer,Neoplasms, Hepatic,Neoplasms, Liver,Cancer, Hepatic,Cancer, Liver,Cancers, Hepatic,Cancers, Hepatocellular,Cancers, Liver,Hepatic Cancers,Hepatic Neoplasm,Hepatocellular Cancers,Liver Cancers,Liver Neoplasm,Neoplasm, Hepatic,Neoplasm, Liver
D009369 Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Neoplasm,Cancer,Malignant Neoplasm,Tumor,Tumors,Benign Neoplasms,Malignancy,Malignant Neoplasms,Neoplasia,Neoplasm,Neoplasms, Benign,Cancers,Malignancies,Neoplasias,Neoplasm, Benign,Neoplasm, Malignant,Neoplasms, Malignant
D003630 Daunorubicin A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS. Daunomycin,Rubidomycin,Rubomycin,Cerubidine,Dauno-Rubidomycine,Daunoblastin,Daunoblastine,Daunorubicin Hydrochloride,NSC-82151,Dauno Rubidomycine,Hydrochloride, Daunorubicin,NSC 82151,NSC82151
D006031 Glycosylation The synthetic chemistry reaction or enzymatic reaction of adding carbohydrate or glycosyl groups. GLYCOSYLTRANSFERASES carry out the enzymatic glycosylation reactions. The spontaneous, non-enzymatic attachment of reducing sugars to free amino groups in proteins, lipids, or nucleic acids is called GLYCATION (see MAILLARD REACTION). Protein Glycosylation,Glycosylation, Protein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D001682 Biological Availability The extent to which the active ingredient of a drug dosage form becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action. Availability Equivalency,Bioavailability,Physiologic Availability,Availability, Biologic,Availability, Biological,Availability, Physiologic,Biologic Availability,Availabilities, Biologic,Availabilities, Biological,Availabilities, Physiologic,Availability Equivalencies,Bioavailabilities,Biologic Availabilities,Biological Availabilities,Equivalencies, Availability,Equivalency, Availability,Physiologic Availabilities

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