ABSTRACT
BACKGROUND: Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition. METHODS: Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development. RESULTS: The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m(-2) min(-1) and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP. CONCLUSION: Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m(-2) min(-1) and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacokinetics , Deoxycytidine/analogs & derivatives , Membrane Transport Proteins/genetics , Neoplasms/genetics , Neoplasms/metabolism , 5'-Nucleotidase/genetics , 5'-Nucleotidase/metabolism , Adult , Aged , Aged, 80 and over , Alleles , Antimetabolites, Antineoplastic/blood , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Deoxycytidine/administration & dosage , Deoxycytidine/blood , Deoxycytidine/pharmacokinetics , Female , Genotype , Humans , Infusions, Intravenous , Leukocytes, Mononuclear/metabolism , Male , Membrane Transport Proteins/metabolism , Middle Aged , Neoplasms/blood , Neoplasms/drug therapy , Young Adult , GemcitabineABSTRACT
The kinetics of oxidation of 15 alpha-methyl-8-aza-16-oxagona-1,3,5(10),13-tetraen-17-on with rat liver microsomal cytochrome P-450 was investigated. The kinetic parameters, Km and Vmax, of the oxidation reaction were found to be equal to 1,3 X 10(-4) M and 4.0 X 10(-7) M X s-1, respectively. Using thin-layer chromatography, mass-spectrometry, PMR-spectroscopy and reciprocal synthesis, it was shown that 3-hydroxy-15 alpha-methyl-8-aza-16-oxagona-1,3,5(10), 13-tetraen-17-on is the main reaction product.
Subject(s)
Azasteroids/metabolism , Cytochrome P-450 Enzyme System/metabolism , Gonanes/metabolism , Microsomes, Liver/metabolism , Steroids, Heterocyclic/metabolism , Animals , Chromatography, Thin Layer , Hydroxylation , Kinetics , Male , Mass Spectrometry , Microsomes, Liver/enzymology , Oxidation-Reduction , Polarography , Rats , Substrate SpecificityABSTRACT
Experimental systems for the hydroxylation of steroids (11-deoxycorticosterone and cholesterol) with reduced electron transfer chain, in which flavoprotein was omitted, were investigated. Incubation of chemically reduced immobilized adrenodoxin either with cytochrome P-45011 beta or cytochrome P-450scc in the presence of substrate of hydroxylation and oxygen yields the specific reaction products, corticosterone or pregnenolone. The catalytic activity of the experimental dienzyme systems proves the possibility of the steroid hydroxylation mechanism based exclusively on dissociation and reassociation of the electron transporting protein complexes.
Subject(s)
Adrenodoxin/metabolism , Cytochrome P-450 Enzyme System/metabolism , Multienzyme Complexes/metabolism , Steroids/metabolism , Adrenal Glands/enzymology , Animals , Cattle , Chromatography, High Pressure Liquid , Enzymes, Immobilized , Hydroxylation , In Vitro Techniques , Mitochondria/enzymologyABSTRACT
The interaction of the 8-aza-16-oxasteroid series (8-AS) with cytochrome P-450 from liver microsomes of intact and phenobarbital-induced rats has been studied. It has been shown that 8-AS are the substrates for the cytochrome P-450-dependent enzyme system, and that their affinity for cytochrome P-450 is determined by the structure of the compounds tested. Using inhibitory analysis, the site in the active center of hemoprotein responsible for 8-AS binding was examined. The possibility of direct participation of the 8-AS ketogroup in their binding with cytochrome P-450 is discussed.
