Quantitative rat liver function test by galactose single point method.

The purpose of this study was to investigate the galactose single point (GSP) method, a residual liver function test recently recommended by the US Food and Drug Administration, which can be a useful tool for rat liver function measurement. Rats were treated either with carbon tetrachloride (CCl(4)) alone (1 mL/kg, intraperitoneally [i.p.]) for one day or with isoniazid (INH) alone (150 mg/kg, i.p.) or (in order to ameliorate the effects of INH) with a combination of INH and bis-p-nitrophenyl phosphate (BNPP) (25 mg/kg, i.p.) for 21 days. Hepatotoxicity was assayed by plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and scores of histological activity index-necroinflammation (HAI-NI) of the respective liver specimens. The GSP method in rats was defined by the galactose blood level after 60 min. Significant differences in GSP values were observed between controls and the CCl(4)-treated rats. After 21 days of treatment, no significant changes in AST and ALT values were observed among the control, INH and INH-BNPP groups. There were significant differences in average GSP values for controls (P < 0.001) and INH-BNPP (P < 0.001) compared with INH alone. Highly significant correlations (P < 0.001) were obtained between GSP and scores of HAI-NI for all the groups. GSP was concluded to be a more sensitive biomarker of INH-induced hepatotoxicity than AST or ALT in the rats. The GSP method has been proved to be a simple and useful tool for the quantitative determination of liver function in rats, which can possibly be extended to other animals.

Statistical and parametric analysis of beta-2-microglobulin removal from uremic patients in high flux hemodialysis.

Beta-2-microglobulin (beta 2M) associated amyloidosis has been seen in patients with chronic renal failure after long-term hemodialysis. However, the exact mechanism of beta 2M formation and accumulation is not clinically understood. In this investigation, the formation and removal kinetics of beta 2M were studied by compartmental modeling of a patient dialyzer system. Statistical and parametric analyses of model equations, coupled with clinical data from selected patients, enabled us to predict the behavior and influence of membrane materials upon the clearance characteristics of beta 2M during and between hemodialysis treatments.

High-performance liquid chromatographic method for the simultaneous determination of nalbuphine and its prodrug, sebacoyl dinalbuphine ester, in dog plasma and application to pharmacokinetic studies in dogs.

For the determination of nalbuphine and its long acting prodrug, sebacoyl dinalbuphine ester (SDN), in biological samples, a reversed-phase high-performance liquid chromatographic method using dual detectors was established. Ultraviolet and fluorescence detectors were connected in series for determining SDN and nalbuphine, respectively. The two analytes and internal standard were extracted from plasma by alkaline liquid-liquid extraction using n-hexane-isoamyl alcohol (9:1, v/v). The calibration curve for nalbuphine was linear over the range from 10 to 2,500 ng/ml, while the range was 25 to 2,500 ng/ml for SDN. The within- and between-day precision and accuracy were all within 10% for both nalbuphine and SDN over these concentrations. The method was applied successfully to a pharmacokinetic study of SDN administered at 20 mg/kg to two beagle dogs. Pharmacokinetic analysis revealed that SDN followed a linear one-compartment model with an elimination half-life of 74.7 min. Formation of nalbuphine after intravenous administration of SDN was observed in the first time point sample (5 min). These results indicate that SDN is rapidly metabolized to its active moiety, nalbuphine, in dogs and no other metabolites are detected in plasma.

Clinical experience and model analysis on beta-2-microglobulin kinetics in high-flux hemodialysis.

Beta-2-microglobulin (beta 2M) is associated with amyloidosis. The study of beta 2M kinetics can provide information on the elimination of this uremic toxin. A beta 2M kinetic model modified from Gotch, considering the volume changes between intracellular, interstitial, and intravascular compartments and the generation stimulation and inhibition during hemodialysis is proposed. The clinical experiments on 8 stable hemodialysis patients treated with polysulfone (F80) and polymethyl methacrylate (PMMA, BK2.1p) 3 times a week were conducted. There was an 18% decrease of beta 2M clearance in the period from 30 to 180 min with a time-averaged beta 2M clearance of 48 ml/min using polysulfone dialyzers (F80). In PMMA dialyzers, there was a 64% decrease of beta 2M clearance from 30 to 180 min with a time-averaged clearance of 56.3 ml/min. During hemodialysis, the generation rate was 0.379 mg/min in polysulfone and 0.828 mg/min in PMMA dialyzers. There was a stimulation generation of 0.309 mg/min in polysulfone and 0.749 mg/min in PMMA during hemodialysis. In conclusion, we provide a beta 2M kinetic model including volume changes, polymerization, generation stimulation, and inhibition that is similar to the human physiological condition. This model can be used for further clinical study.