Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites. 2001

T Kerbusch, and J de Kraker, and H J Keizer, and J W van Putten, and H J Groen, and R L Jansen, and J H Schellens, and J H Beijnen
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/ Slotervaart Hospital, Amsterdam. Thomas.Kerbusch@biof.uu.se

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

UI MeSH Term Description Entries
D007069 Ifosfamide Positional isomer of CYCLOPHOSPHAMIDE which is active as an alkylating agent and an immunosuppressive agent. Isofosfamide,Isophosphamide,Asta Z 4942,Holoxan,Iphosphamide,Iso-Endoxan,NSC-109,724,NSC-109724,Iso Endoxan,NSC 109,724,NSC 109724,NSC109,724,NSC109724
D008751 Methylene Blue A compound consisting of dark green crystals or crystalline powder, having a bronze-like luster. Solutions in water or alcohol have a deep blue color. Methylene blue is used as a bacteriologic stain and as an indicator. It inhibits GUANYLATE CYCLASE, and has been used to treat cyanide poisoning and to lower levels of METHEMOGLOBIN. Methylthionine Chloride,Swiss Blue,Basic Blue 9,Chromosmon,Methylene Blue N,Methylthioninium Chloride,Urolene Blue,Blue 9, Basic,Blue N, Methylene,Blue, Methylene,Blue, Swiss,Blue, Urolene
D003520 Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. (+,-)-2-(bis(2-Chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-Oxide Monohydrate,B-518,Cyclophosphamide Anhydrous,Cyclophosphamide Monohydrate,Cyclophosphamide, (R)-Isomer,Cyclophosphamide, (S)-Isomer,Cyclophosphane,Cytophosphan,Cytophosphane,Cytoxan,Endoxan,NSC-26271,Neosar,Procytox,Sendoxan,B 518,B518,NSC 26271,NSC26271
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005198 Fanconi Syndrome A hereditary or acquired form of generalized dysfunction of the PROXIMAL KIDNEY TUBULE without primary involvement of the KIDNEY GLOMERULUS. It is usually characterized by the tubular wasting of nutrients and salts (GLUCOSE; AMINO ACIDS; PHOSPHATES; and BICARBONATES) resulting in HYPOKALEMIA; ACIDOSIS; HYPERCALCIURIA; and PROTEINURIA. De Toni-Debre-Fanconi Syndrome,Lignac-Fanconi Syndrome,Proximal Renal Tubular Dysfunction,Renal Fanconi Syndrome,Adult Fanconi Syndrome,Fanconi Bickel Syndrome,Fanconi Renotubular Syndrome,Fanconi Syndrome with Intestinal Malabsorption and Galactose Intolerance,Fanconi Syndrome without Cystinosis,Fanconi-Bickel Syndrome,Glycogen Storage Disease XI,Glycogenosis, Fanconi Type,Hepatic Glycogenosis with Amino Aciduria and Glucosuria,Hepatic Glycogenosis with Fanconi Nephropathy,Hepatorenal Glycogenosis with Renal Fanconi Syndrome,Idiopathic De Toni-Debre-Fanconi Syndrome,Luder-Sheldon Syndrome,Neonatal De Toni-Debre-Fanconi Syndrome,Primary Toni-Debre-Fanconi Syndrome,Pseudo-Phlorizin Diabetes,Toni-Debre-Fanconi Syndrome,Bickel Syndrome, Fanconi,Diabete, Pseudo-Phlorizin,Diabetes, Pseudo-Phlorizin,Fanconi Syndrome, Adult,Fanconi Syndrome, Renal,Fanconi Type Glycogenosis,Fanconi-Bickel Syndromes,Lignac Fanconi Syndrome,Luder Sheldon Syndrome,Pseudo Phlorizin Diabetes,Pseudo-Phlorizin Diabete,Renotubular Syndrome, Fanconi,Syndrome, Adult Fanconi,Syndrome, Fanconi,Syndrome, Fanconi Bickel,Syndrome, Fanconi Renotubular,Syndrome, Fanconi-Bickel,Syndrome, Lignac-Fanconi,Syndrome, Luder-Sheldon,Syndrome, Renal Fanconi,Syndromes, Fanconi-Bickel
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D018906 Antineoplastic Agents, Alkylating A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) Alkylating Agents, Antineoplastic,Alkylating Antineoplastic Agents,Alkylating Antineoplastic Drugs,Alkylating Antineoplastics,Alkylating Drugs, Antineoplastic,Antineoplastic Alkylating Agents,Antineoplastic Drugs, Alkylating,Antineoplastics, Alkylating,Antineoplastic Alkylating Drugs,Drugs, Antineoplastic Alkylating

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