Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

OBJECTIVE: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. METHODS: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. RESULTS: The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. CONCLUSIONS: This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

A Study on Drug Interaction between Warfarin and Capecitabine with Special Reference to the Co-Administered Term or the Discontinuation Term of Capecitabine.

We used the prothrombin time international normalized ratio(PT-INR)to investigate the change in degree and term of warfarin following co-administration and after discontinuation of capecitabine. In this study, approximately 3 years of medical records of 7 patients receiving co-administration therapy of warfarin and capecitabine were obtained from 4 hospitals. We observed daily increases in PT-INR values up to peak PT-INR levels following co-administration of warfarin and capecitabine. Interestingly, the peak PT-INR values of 4 of the patients remained remarkably high despite discontinuation of capecitabine. The peak PT-INR values for concomitant warfarin and capecitabine were attained after an average of 31.3 days of usage. When compared with the average PT-INR values attained before co-administration, the PT-INR values following co-administration significantly increased by 3 times (p<0.05). After discontinuation of capecitabine for an average of 15.1 days, i. e., for approximately 14 days, the PT-INR values returned to the PT-INR values attained prior to co-administration. These results suggest that capecitabine has influence on the anticoagulant effect of warfarin during not only the co-administered term but also the discontinuation term, and that this influence occasionally continues after discontinuation of capecitabine. These findings also suggest that a period of approximately 14 days after discontinuation is necessary for the interaction of capecitabine to dissipate and the PT-INR values to return the levels attained before receiving concomitant warfarin and capecitabine.

Expression of the mammalian homologue of vacuolar protein sorting 16 (Vps16p) in the mouse and rat brain.

Synaptic vesicle fusion events are essential for synaptic transmission. Membrane docking and fusion events are highly regulated processes requiring the participation of a large number of soluble N-ethylmaleimide-sensitive factors (SNAREs) and SNARE-interacting proteins. We report the neuronal expression of mammalian homologue of vacuolar protein sorting 16 (mVps16p) which exhibits a high homology to the yeast Vps16p, a component of Class C Vps. Western blot and immunohistochemical analyzes revealed that mVps16p is highly expressed in the various brain areas and developmental stages tested. The immunoreactivities of mVps16p colocalized with microtubule associated protein 2, but not glial fibrillary acidic protein. In the primary culture of cortical neurons, mVps16p immunoreactivities were observed in the cell body and the neuronal processes, and highly enriched in the axonal outgrowths.

Identification of mouse Vps16 and biochemical characterization of mammalian class C Vps complex.

Many multiprotein complexes mediate the fusion of the intracellular membranes. The question how the specificity of the membrane fusion is controlled has not been fully elucidated. Here we report the identification of a mouse homologue Vps16p (mVps16), which exhibits a high homology to the yeast Vps16p, a component of Class C vacuolar protein sorting (Vps) complex implicated in the yeast vacuole membrane fusion. Northern and Western blot analyses reveal that mVps16 is ubiquitously expressed in the mouse peripheral tissues. Biochemical analyses show that mammalian Class C Vps proteins interact with multiple syntaxins and Vps45p, which localizes in the endosomal compartments. The internalization of transferrin (Tf) is not affected by the overexpression of mammalian class C Vps proteins, but the recycling was inhibited. Taken together, this study provides biochemical characteristics of mVps16p in mammalian cells and the potential roles of mammalian Class C Vps proteins in membrane trafficking.