Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics

This paper describes a population pharmacokinetic analysis of a clinical phase I trial of pilocarpine HCl tablet. In the trial, the pharmacokinetics of orally administered pilocarpine HCl were examined in 24 healthy male subjects. A one-compartment model with first-order absorption was adopted and a multivariate log-normal distribution was assumed for the population distribution of the pharmacokinetic parameters. The regression of the distribution volume on the body weight was examined. The maximum likelihood method was employed to estimate the population means, variances and correlation coefficients of the multivariate log-normal population distribution. Instead of the first-order Taylor series approximation, a Monte Carlo integration was used for the multiple integral in the log likelihood. Observations below the detection limit were incorporated via a likelihood term. The population mean estimates for the absorption rate constant k_a, elimination rate constant K and lag time t_lag, were 2.864 (hr^-1), 0.444 (hr^-1) and 0.196 (hr), respectively. The distribution volume V_d was linearly related to the body weight (BW) as V_d (L) =2.959×BW (kg)-23.861. The population standard deviation estimates for k_a, K, V_d and t_lag were 0.764 (log (hr^-1)), 0.197 (log (hr^-1)), 0.169 (log (L)) and 0.346 (log (hr)), respectively.

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The effect of methylprednisolone on the pharmacokinetics of lecithinized SOD (PC-SOD) was examined in mice. Methylprednisolone was simultaneously administered with [³H] PC-SOD, however there was no significant difference in the pharmacokinetics of [³H] PC-SOD. At 24 hr, the distribution of [³H] PC-SOD in some tissues was minimally changed. These results suggest that methylprednisolone has little influence on the biodistribution of PC-SOD, and co-administration of the two shows an additive pharmacological effect in clinical study.

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Objectives: We studied the gender effects on the pharmacokinetics and pharmacodynamics of a single dose of nitrazepam in Japanese healthy volunteers.
Methods: Eight healthy young females and males were included in a placebocontrolled double-blinded two-way cross-over study after giving written informed consent. The effects of a single dose of 5 mg nitrazepam were evaluated using computerized eye movement analysis and visual analogue scales (VAS) based on the classification of Norris et al. Blood samples were collected at the times indicated in the protocol and serum concentrations of nitrazepam were assayed by HPLC.
Results: The time to reach maximum concentration of nitrazepam tended to be prolonged in females compared with males. The half-life of serum nitrazepam was significantly shorter in females than in males. There was no gender difference in the decrease of saccadic peak velocity after nitrazepam intake but its recovery to the baseline level tended to be delayed in females. Control values of smooth pursuit eye movement were significantly lower in females but the effect of nitrazepam was similar in both genders. The subjective effects of nitrazepam were marked in females on mental or physical sedation evaluated with VAS.
Discussion: There were gender differences in some parameters of pharmacokinetics and pharmacodynamics of nitrazepam. The effects of menstrual cycle on the drug effects remain to be clarified. Since most medicines are applied to both males and females, we should accumulate more information on specific medicines in both males and females.

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