The validity of pharmacokinetic parameters estimated by the maximum a posteriori probability (MAP) Bayesian method was investigated by simulation studies. A 1-compartment model with bolus intravenous administration was used as a pharmacokinetic model, and the coefficients of variation for the parameters and residual error were set at 30% and 10%, respectively. The accuracy of the posterior modes of pharmacokinetic parameters estimated by the MAP Bayesian method was assessed by the difference between the true value and the estimated value. The results showed that the accuracy of the Bayesian estimation depended on sampling times and on the differences between the prior means and individual true parameter values. For assessing the reliability and accuracy of the Bayesian estimation, the authors suggest using the whole posterior distribution of the pharmacokinetic parameters to describe the 95th percentile range for predicted blood concentration profiles. The authors believe that the proposed procedures provide helpful information for evaluating the Bayesian estimation of pharmacokinetic profiles.
To investigate the mechanism underlying the protective effect against cisplatin (CDDP) nephrotoxicity of its antidote, sodium thiosulfate (STS), the effects of STS on the pharmacokinetics of unchanged CDDP and on the distribution of unchanged CDDP and high and low molecular mass metabolites (fixed and mobile metabolites) in the kidney 1 min after a bolus injection of CDDP (5 mg/kg) to rats were studied. A decrease in the plasma concentration of unchanged CDDP and an increase in the plasma concentration of mobile metabolites were observed in the rats after the bolus injection of CDDP in combination with STS infusion for 30 min (1200 mg/kg). Although STS accelerated platinum excretion during the first 10 min after CDDP injection, unchanged CDDP was not excreted in the urine in the STS-treated rats. Total kidney platinum 1 min after the bolus injection of CDDP was detected mainly as unchanged CDDP (86% of the total platinum) in the rats given CDDP alone. However, in the STS-treated rats, the total kidney platinum was decreased to 62% of the level in the rats given CDDP alone, and the platinum species detected in the kidney were mainly mobile metabolites. Only 24% of the total kidney platinum was detected as unchanged CDDP in the STS-treated rats. The loss of body weight and increases in BUN and serum creatinine levels usually observed after a bolus injection of CDDP were completely prevented by STS coadministration. The present study provides information about unchanged CDDP pharmacokinetics and the distribution of unchanged CDDP and some of its generic metabolites in the kidney when STS is coadministered as an antidote. These results show that the protective effect of STS against CDDP nephrotoxicity can be attributed to the formation of inactive mobile metabolites by a direct reaction between unchanged CDDP and STS in the systemic circulation, resulting in a reduction in the amount of unchanged CDDP in the kidney.
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