[Pharmacokinetics of tramadol hydrochloride in the extracellular fluid of mouse frontal cortex studied by in vivo microdialysis].

The paper aims to explore the studying method for the pharmacokinetics of drugs in target organs, the pharmacokinetic process of tramadol hydrochloride in the extracellular fluid of frontal cortex (FrCx) of mice was investigated. Six male mice (Kunming strain) were anaesthetized (urethane, 1.8 g x kg(-1), ip) and secured on a stereotaxic frame. A microdialysis probe was implanted into the FrCx and perfused with artificial cerebrospinal fluid at a flow rate of 2 microL x min(-1). One hour later, mice were administrated (ip) with tramadol hydrochloride (50 mg x kg(-1)) and dialysates were collected continuously at 12-min intervals (24 microL each) for 6 h. The tramadol concentration in dialysates was determined by HPLC-Ultraviolet detection method, and the concentration-time curve and pharmacokinetic parameters of tramadol were calculated with DAS software. The results showed that the pharmacokinetic process of tramadol in the FrCx extracellular fluid of mice was fitted to a two-compartment open model, and the main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-infinity) were (0.27 +/- 0.05) h, (2.72 +/- 0.24) h, (0.50 +/- 0.10) h, (2 110.37 +/- 291.22) microg x L(-1) and (4 474.51 +/- 441.79) microg x L(-1) x h, respectively. In conclusion, a studying method for pharmacokinetics of drugs in the target organ is established, which is simple and feasible. Tramadol hydrochloride shows a two-compartment model in the extracellular fluid of the mouse FrCx, and the distribution- and elimination half-life are 0.5 h and 2.7 h, respectively.

[Pharmacokinetics--pharmacodynamics of modafinil in mice].

To guide the reasonable clinical application of modafinil (MOD), pharmacokinetics and pharmacodynamics of MOD in mice and the correlation between them were investigated. Male mice (Kunming strain) were given a single oral dose of MOD (120 mg x kg(-1)). The plasma concentration of MOD was measured by HPLC and the pharmacokinetic parameters were calculated with DAS 3.0 software. For another batch of male Kunming strain mice, their locomotor activities were recorded by an infrared ray passive sensor after a same oral dose of MOD, and the synchronization and correlation between the changes of MOD plasma concentration and the locomotor activity induced by MOD were compared and analyzed. The results showed that the plasma concentration-time curve of MOD was fitted to two-compartment open model with a first order absorption. The main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-inifinity) were 0.42 h, 3.10 h, 1.00 h, 41.34 mg x L(-1) and 142.22 mg x L(-1) x h, respectively. MOD significantly increased locomotor activity and the effect lasted for about 4 h. The changes of MOD plasma concentration and the locomotor activity induced by MOD were synchronous. In conclusion, there is a significant correlation between the effect of MOD and its plasma concentration after administration of 120 mg x kg(-1) in mice.

Hepatotoxicity and toxicokinetics of ketoconazole in rabbits.

AIM: To study the relationship between hepatotoxicity and toxicokinetics of ketoconazole in rabbits. METHODS: Normal rabbits were given intragastric gavage ketoconazole 40, 80, and 160 mg/kg. Ketoconazole plasma concentrations were measured by high performance liquid chromatography. Toxicokinetic parameters were determined from the plasma concentration-time data with the 3P97 software package. Activities of serum glutamate-pyruvate-transaminase and glutamate-oxalate-transaminase and hepatic histopathological changes were observed at 36 h after administration. The relationship between hepatotoxicity and toxicokinetic parameters of ketoconazole was analyzed by linear correlation. RESULTS: The concentration-time curves of three doses of ketoconazole fitted well into a two-compartment model. The proportional increase in the area under the plasma concentration-time curve (AUC) was more than that in the dose after the dose reached 80 mg/kg. Ketoconazole resulted in a marked elevation in the enzyme activities and significant damage of hepatocytes. Hepatotoxicity induced by ketoconazole was correlated to the dose, clearance (CL), maximum plasma concentration (Cmax), and most closely correlated to AUC when it was assessed by elevation transaminases in serum. CONCLUSION: The severity of ketoconazole-induced hepatotoxicity was closely related to the exposure level (AUC) of the drug.