Pharmacokinetics of Atorvastatin and Its Hydroxy Metabolites in Rats and the Effects of Concomitant Rifampicin Single Doses: Relevance of First-Pass Effect From Hepatic Uptake Transporters, and Intestinal and Hepatic Metabolism

Abstract

ABSTRACT:Pharmacokinetic coadministration experiments with atorvastatin (ATV) and rifampicin (RIF) in rats were performed to investigate the potential involvement of hepatic uptake transporters, Oatps (organic anion-transporting polypeptides), during hepatic drug elimination, as an in vivo extension of our recently published cellular and isolated perfused liver studies. ATV was administered orally (10 mg/kg) and intravenously (2 mg/kg) to rats in the absence and presence of a single intravenous dose of RIF (20 mg/kg), and pharmacokinetic parameters were compared between control and RIF-treatment groups. RIF markedly increased the plasma concentrations of ATV and its metabolites when ATV was administered orally. The area under the plasma concentration-time curve (AUC 0-ؕ ) for ATV also increased significantly after intravenous dosing of ATV with RIF, but the extent was much less than that observed for oral ATV dosing. Significant increases in plasma levels were observed for both metabolites as well. The 7-fold higher AUC ratio of metabolites to parent drug following oral versus intravenous ATV dosing suggests that ATV undergoes extensive gut metabolism. Both hepatic and intestinal metabolism contribute to the low oral bioavailability of ATV in rats. In the presence of RIF, the liver metabolic extraction was significantly reduced, most likely because of RIF's inhibition on Oatp-mediated uptake, which leads to reduced hepatic amounts of parent drug for subsequent metabolism. Gut extraction was also significantly reduced, but we were unable to elucidate the mechanism of this effect because intravenous RIF caused gut changes in availability. These studies reinforce our hypothesis that hepatic uptake is a major contributor to the elimination of ATV and its metabolites in vivo.Bioavailability of orally administered drugs is often limited by first-pass effects because of metabolism and transporter-mediated processes. In clinical studies, significant interactions between the cholesterol-lowering agent, atorvastatin (ATV), and cytochrome P450 3A (CYP3A) inhibitors such as itraconazole (Kantola et al., 1998) and erythromycin (Siedlik et al., 1999) were observed, with increased area under the plasma concentration-time curve (AUC) of ATV and reduction in the AUC values of its active metabolites ortho-or 2-hydroxy atorvastatin (2-OH ATV) and para-or 4-hydroxy atorvastatin (4-OH ATV). These results suggest extensive contribution of CYP3A toward ATV metabolism in vivo, even though other isoforms such as CYP2C8 have also been shown to metabolize ATV at a slower rate (Jacobsen et al., 2000). In humans, the absolute bioavailability of ATV is only 12% (Gibson et al., 1997), possibly as a result of substantial metabolism in both gut and liver by CYP3A4, the most abundant P450 enzyme expressed in both tissues. Our laboratory has noted that the two major active oxidative metabolites of ATV were formed during incubation with both human intestinal and hepatic microsomes Jacobsen et al., 2000).Various cell-based studies have suggested th...

Quantitative intravital microscopy of hepatic transport

“…This result is consistent with previous studies in which rifampin has been found to inhibit hepatic uptake in cultured rat hepatocytes 51 and perfused rat liver. 53 However, our results are novel in that they, (1) demonstrate that rifampin blocks uptake by hepatocytes in the intact liver in vivo, (2) demonstrate that rifampin blocks the initial step of uptake into the cytosol and (3) demonstrate that inhibition delivery of bilirubin to the hepatocyte cytosol, where conjugation occurs, this is a surprising result. In the model used to explain these results, the authors suggest that organic anion transporters mediate re-uptake of bilirubin that is refluxed by hepatocytes after conjugation (via Mrp3 and/or Mrp4).…”

“…This result contrasts with previous fluorescence microscopy studies indicating that rifampin reduces canalicular secretion of dichlorofluorescein in cultured hepatocytes 55,56 and studies of transfected cell systems indicating that rifampin blocks human and rat MRP2-mediated transport. 53,55,56,58 The basis of this difference is unclear, but may reflect differences between the in vitro and in vivo context of the different studies.…”

“…In order to demonstrate the sensitivity of the liver transport assays, we evaluated transport in rats treated for 4 d with rifampin, an antibiotic used to treat tuberculosis, and a potent inhibitor of rat and human organic anion transporters. [50][51][52][53][54] The time course of fluorescein redistribution over 6 min in rifampintreated and vehicle-treated control rats is shown in Figure 3. The top three panels show that, similar to the results shown in Figure 2, fluorescein rapidly redistributes from the sinusoids into the hepatocyte cytosol and canaliculi in a control rat.…”

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

“…Previous clinical studies have also reported an increase in the exposure of atorvastatin lactone after treatment with known inhibitors of OATP1B1, for instance, CsA and rifampin (Hermann et al, 2004;Lemahieu et al, 2005;Lau et al, 2006). Lau et al (2006) suggested that this observation could be explained by the lactone form being a substrate for OATP1B1 as well.…”

Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

“…6,7 ATR is reported to have pH dependent solubility. 8 The drug undergoes high intestinal clearance and first-pass metabolism 9 resulting in low absolute and systemic bioavailability which is about 14% and 30%, respectively. 10,11 Different formulation strategies for ATR have been reported to improve the solubility such as self-emulsifying drug delivery systems, 12 self-micro emulsifying drug delivery systems, 13 self-nano emulsifying drug delivery systems, 14 conversion into amorphous nanoparticles using supercritical anti-solvent process, 15 and micronization using anti-solvent precipitation process, 16 but none of the formulation techniques were intended to modify or to enable sustain release of ATR along with limitations for their use.…”