Pravastatin transport across the hepatocyte canalicular membrane requires both ATP and a transmembrane pH gradient.

Hepatic excretion of non-bile acid organic anions is reported to be ATP-dependent and a defect of this transport has been reported in congenitally jaundiced rats, animal models of human Dubin-Johnson syndrome. To investigate the effect of the transmembrane pH gradient on hepatocyte canalicular membrane transport of ATP-dependent organic anions, uptake of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase-inhibiting organic anion, by hepatocyte canalicular membrane vesicles was observed in the presence or absence of transmembrane pH gradients. Uptake was assessed by a rapid filtration technique. ATP-dependent pravastatin uptake was stimulated in the presence of a transmembrane pH gradient (in > out) in Sprague-Dawley (SD) rats. Uptake was dependent on both pravastatin and ATP concentrations and showed saturation kinetics. After intravenous injection of [14C]-pravastatin (0.3 mumol), 81% of the dose was excreted in the bile within 35 min in SD rats, whereas only 20% was excreted in the bile in Eisai hyperbilirubinuria rats. ATP and the pH gradient also co-stimulated the uptake of pravastatin in Eisai hyperbilirubinuria rats, although the K(m) was much higher and Vmax was much lower than corresponding values in SD rats. This coincided well with the marked reduction in vivo biliary excretion of pravastatin in jaundiced rats.

Mutagenicity of airborne particulates in Sagamihara City.

Airborne particulates in Sagamihara city were collected on quartz fibre filters using a high-volume air sampler for 14 days in each month from July 1984 to June 1985. Organic components in airborne particulates were extracted by the ultrasonic extraction method using benzene-ethanol (3:1 v/v) as an extracting solvent. The mutagenecities of airborne particulates extract were measured by the pre-incubation method using Salmonella typhimurium strains TA100 and TA98 with and without S-9mix. The concentration of airborne particulates was nearly the same level throughout the survey period, but the content of extract in particulates of winter was higher than those of other seasons. All the airborne particulates extracts showed positive mutagenic response to both strains with and without S-9mix. The average of mutagenic activities (revertants/m3 air) in winter was significantly higher than those in summer and spring. Furthermore, mutagenic activities fluctuated sharply in one month from several to ten times compared with the normal level, depending upon sampling days, and tended to be lower on Sundays and holidays in summer and new year holidays. In many days mutagenic activities without S-9mix were comparatively higher than those with S-9mix. The existence of nitroarene was surveyed using TA98NR strain. Nitroarene was found to be higher concentration in summer than in winter.