Investigation of the Rate-Determining Process in the Hepatic Elimination of HMG-CoA Reductase Inhibitors in Rats and Humans

Abstract

ABSTRACT:Elucidation of the rate-determining process in the overall hepatic elimination of drugs is critical for predicting their intrinsic hepatic clearance and the impact of variation of sequestration clearance on their systemic concentration. The present study investigated the rate-determining process in the overall hepatic elimination of the HMG-CoA reductase inhibitors pravastatin, pitavastatin, atorvastatin, and fluvastatin both in rats and humans. The uptake of these statins was saturable in both rat and human hepatocytes. Intrinsic hepatic clearance obtained by in vivo pharmacokinetic analysis in rats was close to the uptake clearance determined by the multiple indicator dilution method but much greater than the intrinsic metabolic clearance extrapolated from an in vitro model using liver microsomes. In vivo uptake clearance of the statins in humans (pravastatin, 1.44; pitavastatin, 30.6; atorvastatin, 12.7; and fluvastatin, 62.9 ml/ min/g liver), which was obtained by multiplying in vitro uptake clearance determined in cryopreserved human hepatocytes by rat scaling factors, was within the range of overall in vivo intrinsic hepatic clearance (pravastatin, 0.84-1.2; pitavastatin, 14-35; atorvastatin, 11-19; and fluvastatin, 123-185 ml/min/g liver), whereas the intrinsic metabolic clearance of atorvastatin and fluvastatin was considerably low compared with their intrinsic hepatic clearance. Their uptake is the rate-determining process in the overall hepatic elimination of the statins in rats, and this activity likely holds true for humans. In vitro-in vivo extrapolation of the uptake clearance using a cryopreserved human hepatocytes model and rat scaling factors will be effective for predicting in vivo intrinsic hepatic clearance involving active uptake.Predicting the pharmacokinetic properties of drug candidates in preclinical stages of development has been a critical issue for avoiding failure in clinical stages of development because of pharmacokinetics. The liver is the major clearance organ for drugs in the body where the inactivation mechanisms are composed of metabolic enzymes and drug transporters. These inactivation mechanisms are associated with the hepatic first-pass effect after oral administration and with elimination from the systemic circulation. It is well accepted that, because of large species differences in drug metabolism, the results of animal studies cannot be directly extrapolated to humans. Instead, in vitro systems have been developed to replace animal studies and provide reliable predictions. In particular, human liver microsomes enable the reliable prediction of the metabolic clearance of drugs in the liver of humans (Iwatsubo et al

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

“…Renally eliminated compounds that are substrates for P-gp, which is present in both the liver and kidney among many other tissues, might not be substrates for hepatic uptake transporters, and are therefore not biliarily accessible. As others have hypothesized, hepatic uptake, particularly by OATPs, may be a rate-limiting step in biliary excretion (5,8). Indeed, acrivastine and levocetirizine were not found to be substrates of major hepatic uptake transporters in the literature.…”

“…While human liver microsomes generally provide reliable predictions of human metabolic clearance for extensively metabolized drugs (8)(9)(10)(11)(12)(13) and renal clearance is not difficult to determine, predictions of human biliary clearance are difficult and scarce, despite ongoing efforts (14). Clinical methods include bile duct cannulation during surgery, collection of duodenal fluid in healthy volunteers, or fecal collections.…”

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

“…All of these results suggested that the enhanced activity and expression of hepatic Cyp3a were the main contributors to the increases in systemic clearance of simvastatin and simvastatin acid. The uptake of drugs by hepatocytes is also considered a rate-determining process in the hepatic clearance of statins via OATPs [33,34] . The uptake of simvastatin by hepatocytes and the expression of Oatp2 were also investigated.…”

“…Uptake of simvastatin by hepatocytes Uptake of statins by hepatocytes is considered a ratedetermining process in the overall hepatic elimination of statins [33,34] . The uptake of simvastatin by hepatocytes was investigated using freshly isolated rat hepatocytes from experimental rats ( Figure 3D).…”

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…19) Regarding statins, Watanabe et al have demonstrated that the overall hepatic clearance of 4 statins, pitavastatin, rosuvastatin, atorvastatin and fluvastatin is mainly dominated by the hepatic uptake process. 20) Pitavastatin and rosuvastatin are not metabolized in rats and mainly excreted into bile in an unchanged form, whereas atorvastatin and fluvastatin, which are both reported to be OATP substrates, are extensively metabolized by CYP3A4 and CYP2C9, respectively. In vivo hepatic clearances of these statins were well correlated with in vitro uptake intrinsic clearances obtained with isolated hepatocytes, but poorly correlated with in vitro metabolic intrinsic clearances obtained with liver microsomes.…”