Uptake is the rate-limiting step in the overall hepatic elimination of pravastatin at steady-state in rats.
OBJECTIVE
Of the HMG-CoA reductase inhibitors, the hydrophilic pravastatin has been shown to exhibit relatively specific inhibition of cholesterol synthesis in the liver. As one of the reasons for this relatively specific pharmacological activity, we demonstrated that the tissue distribution of pravastatin is limited because of its high hydrophilicity, while hepatic uptake by active transport takes place at the liver surface via a multispecific anion transporter (M. Yamazaki et al., Am. J. Physiol., 264, G36-44, 1993). In this study, we examined the hepatic elimination of pravastatin at steady-state.


METHODS
After i.v. infusion, the plasma concentrations of pravastatin in both arterial and hepatic venous blood were measured.


RESULTS
The hepatic availability at steady-state exhibited a clear increase on increasing the infusion rate of pravastatin. The total hepatic elimination rate at steady-state exhibited Michaelis-Menten type saturation with the drug concentration in the capillary defined by typical mathematical models (i.e., well-stirred, parallel-tube and dispersion models), K(m) and Vmax values being comparable with those obtained from analysis of the initial uptake velocity using in vitro isolated hepatocytes.


CONCLUSIONS
These results indicate that overall hepatic intrinsic clearance of pravastatin at steady-state is regulated by the uptake process, followed by rapid metabolism and/or biliary excretion with minimal efflux to the circulating blood.
Yamazaki
M
M
Department of Pharmacokinetics and Biopharmaceutics, Toho University, School of Pharmaceutical Sciences, Chiba, Japan.
Akiyama
S
S
Nishigaki
R
R
Sugiyama
Y
Y
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D008432:Mathematical Computing; D008954:Models, Biological; D017035:Pravastatin / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D001798:Blood Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin