Pharmacokinetics of (R)- and (S)-cyclophosphamide and their dechloroethylated metabolites in cancer patients.

The complete pharmacokinetics (PK) of (R)- and (S)-cyclophosphamide (CP) and their dechloroethylated (DCE) metabolites have not been reported to date. We collected plasma and urine samples from 12 cancer patients and determined concentrations of both enantiomers of CP and DCE-CP using a chiral GC-MS method. All concentrations of (R)-CP, (S)-CP, (R)-DCE-CP, and (S)-DCE-CP were simultaneously modeled using an enantiospecific compartmental PK model. A population PK analysis was performed. Enantiospecific differences between (R)- and (S)-CP were found for the formation clearance of CP to the DCE metabolites (Clf: 0.25 (R) vs. 0.14 (S) L/h). No difference was found between enantiomers for Cl40H, Cld, Cl(m)R, ClT, or T1/2. In contrast to the adolescent and adult group of patients, a child (6 years old) appeared to have a very different PK and metabolic profile (Bayesian control analysis). Proportions of the (R,S)-CP doses transformed to the (R)-DCE- and (S)-DCE-CP were much higher (R: 25 vs. 1.9%, and S: 38 vs. 3.6%), while formation of active metabolites was much lower (R: 42 vs. 74%, and S: 48 vs. 77%). CP appears to be enantioselectively metabolized to the DCE metabolites. This PK model can evaluate the proportion of a CP dose that is transformed to toxic or active metabolites. It may therefore be used to optimize CP treatment, to identify important drug interactions and/or patients with an abnormal metabolic profile.

Phenytoin-induced alteration in the N-dechloroethylation of ifosfamide stereoisomers.

CASE: A suspected alteration in ifosfamide (IFF) metabolism and pharmacokinetics was observed in a pediatric patient receiving phenytoin. METHODS: Sequential plasma samples were obtained and analyzed for the concentrations of the enantiomers of IFF and their N-dechloroethylated metabolites (DCE-IFF) using a validated enantioselective gas chromatographic-mass spectrometric method. RESULTS: In the phenytoin-treated patient, the metabolic formation of IFF enantiomers was increased and the metabolic pattern of the N-dechloroethylation altered from non-phenytoin-treated patients: (R)-3-DCE IFF > > (S)-3-DCE-IFF = (S)-2-DCE-IFF > (R)-2-DCE-IFF (control) vs (S)-3-DCE-IFF = (S)-2-DCE-IFF > (R)-3-DCE-IFF > > (R)-2-DCE-IFF (patient). CONCLUSIONS: Previous studies have attributed the production of the (S)-2-DCE-IFF and (S)-3-DCE-IFF metabolites to the activity of CYP2B6 and (R)-2-DCE-IFF and (R)-3-DCE-IFF to the activity of CYP3A4. The results suggest that phenytoin induced the activity of CYP2B6 to a greater extent than CYP3A4. In addition, the patient, who was at least partially refractory to several other treatments, went into remission after IFF treatment suggesting that phenytoin pretreatment might increase IFF therapeutic efficacy.

Migration of secondary tert-butyldimethylsilyl groups in cyclomalto-heptaose and -octaose derivatives.

When 2,6-di-O-tert-butyldimethylsilylated cyclomalto-oligosaccharides (cyclodextrins) are treated with allyl or methyl iodide and NaH in dry tetrahydrofuran, O-2-->O-3 migration of the secondary 2-O-tert-butyldimethylsilyl groups occurs, leading to 2-O-alk(en)yl-3,6-di-O-tert-butyldimethylsilyl-cyclodextrin derivatives. The detection and identification of the reaction step during which migration occurred is described and possible mechanisms of migration are discussed.

Determination of the enantiomeric composition of mexiletine and its four hydroxylated metabolites in urine by enantioselective capillary gas chromatography.

The enantiomers of mexiletine and four of its hydroxylated metabolites were directly separated by capillary gas chromatography using a heptakis(6-O-tert-butyl-dimethylsilyl-2,3-di-O-methyl)-beta- cyclodextrin column. The method was applied to the analysis of urine samples from cancer patients who were treated with racemic mexiletine as part of a study of the use of mexiletine in the relief of neuropathic pain. Samples analyzed before and after deconjugation of the urine with beta-glucuronidase/arylsulfatase showed a high stereoselectivity in the formation and conjugation of these compounds.

Determination of the enantiomers of ifosfamide and its 2- and 3-N-dechloroethylated metabolites in plasma and urine using enantioselective gas chromatography with mass spectrometric detection.

A rapid, sensitive, enantioselective gas chromatographic method has been developed for the quantitation of the enantiomers of ifosfamide (IFF) and its 2- and 3-dechloroethylated metabolites (2-DCE-IFF and 3-DCE-IFF) in human and animal plasma and human urine. IFF and the two dechloroethylated metabolites were extracted into chloroform, enantioselectively resolved by gas chromatography on a chiral stationary phase based upon heptakis(2,6-di-O-methyl- 3-O-pentyl)-beta-cyclodextrin and quantitated using mass-selective detection with selected-ion monitoring. The limits of quantitation for the enantiomers of IFF, 2-DCE-IFF and 3-DCE-IFF in plasma were 250 and 500 ng/ml respectively. In urine, the limits of quantitation for the enantiomers of IFF, 2-DCE-IFF and 3-DCE-IFF were 500 ng/ml. The method can detect concentrations as low as 250 ng/ml of each enantiomer of 2- and 3-DCE-IFF in plasma and urine. The intra- and inter-day coefficients of variation for this method were with one exception less than 8%. The assay was validated for enantioselective pharmacokinetic studies in humans and rats and is the first reported enantioselective assay for the measurement of the enantiomers of 2- and 3-DCE-IFF in plasma.