Masami Kawahara

Effect of Meropenem on Disposition Kinetics of Valproate and Its Metabolites in Rabbits

AbstractPurpose. We investigated the effect of meropenem (MEPM) on the disposition kinetics of valproate (VPA) and its metabolites in rabbits. Methods. Rabbits were given 75 mg/kg VPA intravenously with or without 300 mg/kg MEPM. Results. The plamsa total clearance of VPA was significantly increased to about 1.5 times the control (6.09 mL/min/kg vs. 4.28 mL/min/kg) by MEPM (P < 0.05). The values of the area under the plasma concentration-time curve (AUC) of 2-en-VPA, a product of β-oxidation, and VPA-glucuronide (VPA-G) were significantly decreased to about 55% and 78% of the control, respectively (P < 0.05). The cumulative urinary excretions of VPA in the control and MEPM-treated groups were 0.54% and 0.62% of the dose, respectively, whereas those of VPA-G were 45.6% and 62.5%, respectively. The urinary excretion of VPA-G was significantly increased by MEPM (P < 0.05). Further, in the case of 33.8 mg/kg VPA-G administered intravenously the AUC value of VPA-G was unchanged by MEPM, whereas that of the generated VPA was significantly decreased to about half of the control. Conclusions. The increase of the total clearance of VPA caused by MEPM appears to be a consequence of increased renal clearance of VPA-G, as well as suppression of VPA-G hydrolysis in the liver.

Physiologically based pharmacokinetic prediction of p ‐phenylbenzoic acid disposition in the pregnant rat

Disposition of p ‐phenylbenzoic acid (PPBA) in the pregnant Wistar rat (for both mother and fetuses) was predicted by using a physiologically based pharmacokinetic model. This model was constructed from ten organs for the mother and eight organs for fetuses, with fetal blood flow based on anatomical circulation in uteri and skin–amniotic fluid drug exchange. Plasma total clearance, and renal and nonrenal clearances were measured, and transplacental clearance, skin–amniotic fluid clearances and fetal metabolic clearance were taken from previously reported compartment analysis. Tissue‐to‐plasma partition coefficients (Kp) for the mother were almost the same as that of the interstitial fluid space (0.055–0.28), except for the kidney and liver. In contrast, Kp values for fetuses were small when membrane restricted and diffusion‐limited uptakes were assumed in brain, gut, spleen, muscle, fat, and skin for the mother. The physiological model successfully predicted the PPBA concentration–time profiles for both mother and fetuses after intravenous injection into the mother. Further, the model could be applied to predict the results obtained via two other routes of administration. Fetal plasma PPBA concentrations were well predicted after PPBA injection into umbilical vein and fetal muscle.

Impact of serum caffeine monitoring on adverse effects and chemotherapeutic responses to caffeine-potentiated chemotherapy for osteosarcoma

BackgroundCaffeine can safely enhance the cytocidal effects of anticancer drugs through its DNA repair-inhibiting effect. We have demonstrated in several studies that caffeine-potentiated chemotherapy induces a high complete response rate in patients with osteosarcoma. The present study focused on monitoring and adjusting serum caffeine levels during caffeine-potentiated chemotherapy to reduce adverse effects.MethodsWe utilized a method for rapidly determining caffeine concentration by high-performance liquid chromatography. The maximum caffeine concentration was predicted from the measured concentrations at 24 and 48 h after the beginning of caffeine administration. The caffeine infusion rate was then modified accordingly to prevent the expected final concentration from exceeding 80 μg/ml. The study involved 22 American Joint Committee on Cancer (AJCC) stage IIB high-grade osteosarcoma patients treated with caffeine-potentiated chemotherapy. Nine patients underwent monitoring of their serum caffeine levels (monitoring group), and the remaining 13 patients were not monitored (nonmonitoring group). Toxicities were graded according to the Japan Clinical Oncology Group Toxicity Criteria.ResultsHematological toxic events were well tolerated in both groups. Grade 4 leukocyte toxicity events occurred in both groups. In the nonmonitoring group grade 2 or higher toxicities included 5 elevated aspartate aminotransferase/alanine aminotransferase level events and 17 hyponatremia events versus 1 hyponatremia event in the monitoring group. Histological examination of excised tumor samples after preoperative chemotherapy revealed that chemotherapeutic efficacy in the monitoring group was as good as in the nonmonitoring group. The median follow-up period in all patients was 72 months. Event-free survival was 76%, and overall survival was 100%.ConclusionsMonitoring and adjusting caffeine levels were achieved without apparent loss of chemotherapeutic efficacy.

Causative agent of vascular pain among photodegradation products of dacarbazine.

The photodegradation products of the anticancer drug, dacarbazine, cause adverse reactions including local venous pain when injected intravenously. In this study, we attempted to identify which of these products is responsible. We synthesized or purchased five photodegradation products of dacarbazine (dimethylamine, 5‐diazoimidazole‐4‐carboxamide (Diazo‐IC), 4‐carbamoylimidazolium‐5‐olate, 5‐carbamoyl‐2‐(4‐carbamoylimidazol‐5‐ylazo) imidazolium‐5‐olate and 2‐azahypoxanthine) and examined the pain reaction induced by their intraperitoneal administration in mice using an abdominal stretching or constriction assay. Only Diazo‐IC clearly induced pain reaction in mice in a dose‐dependent manner, the other products caused no pain reaction. The threshold concentration for pain reaction in mice was estimated to be about 0.1 mg mL−1. While diclofenac sodium significantly reduced acetic‐acid‐induced pain reaction in mice, it did not influence those induced by Diazo‐IC. This result suggests that the mechanism of Diazo‐IC‐induced pain is different from that of acetic‐acid‐induced inflammatory pain. Dacarbazine itself produced marked relaxation of rat thoracic aorta strips in a concentration‐dependent manner, but there was no difference between the activity of dacarbazine and its photo‐exposed solution, so constriction or relaxation of blood vessels is unlikely to be a factor in the pain reaction. In conclusion, Diazo‐IC generated by photodegradation of dacarbazine solution causes the side‐effect of venous pain. Dacarbazine solution that has turned pink should not be used, because Diazo‐IC is an intermediate in the formation of the reddish product, 5‐carbamoyl‐2‐(4‐carbamoylimidazol‐5‐ylazo) imidazolium‐5‐olate. Drip infusion preparations of dacarbazine should be shielded from light.