Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase

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Abstract

Aim

The aim of this study was to investigate the biliary secretion of rosuvastatin in healthy volunteers using an intestinal perfusion method after administration of 10 mg rosuvastatin dispersion in the intestine.

Methods

The Loc-I-Gut tube was positioned in the distal duodenum/proximal jejunum and a semi-open segment was created by inflating the proximal balloon in ten volunteers. A dispersion of 10 mg rosuvastatin was administered below the inflated balloon and bile was collected proximally of the inflated balloon. Bile and plasma samples were withdrawn every 20 min during a 4 h period (absorption phase) and additional plasma samples were collected 24 and 48 h post-dose.

Results

The study showed that there is a substantial and immediate transport of rosuvastatin into the human bile, with the maximum concentration appearing 42 min after dosing, 39,000 ± 31,000 ng/ml. Approximately 11% of the administered intestinal dose was recovered in the bile after 240 min. At all time points the biliary concentration exceeded the plasma concentration, and the average bile to plasma ratio was 5200 ± 9200 (range 89–33,900, median 2000). We were unable to identify any bile-specific metabolites of rosuvastatin in the present study.

Conclusion

Rosuvastatin is excreted via the biliary route in humans, and the transport and accumulation of rosuvastatin in bile compared to that in plasma is rapid and extensive. This intestinal perfusion technique offers a successful way to estimate the biliary secretion for drugs, metabolites and endogenous substances during the absorption phase in healthy volunteers.

Introduction

The impact of carrier-mediated membrane transport of drugs on their absorption, first-pass liver extraction, and disposition is not well established in vivo owing to the complexity associated with it and relevant in vivo based data are therefore often lacking, as a result of which one is generally restricted to in vitro based data (Meijer and Lennernas, 2005). Furthermore, an increasing awareness of drug induced hepatotoxicity has resulted in a focus on investigating local liver exposure of drugs and metabolites as an important part of drug development (Lee, 2003). For instance, a population-based study performed in France indicated an underestimation of the reports of hepatic adverse drug events (hepatic ADR) by the regulatory authorities of 16 times, and the incidence rate of hepatic ADR was 13.9 in 100,000 habitants per year (Sgro et al., 2002). Consequently, a model enabling direct determinations to be made of the in vivo kinetics of intestinal and hepatobiliary transport and the metabolism of drugs would be a valuable tool. The use of such a model could increase our understanding of the mechanisms underlying the processes determining the bioavailability, local liver exposure and drug–drug interactions, and therefore have an impact on pharmacokinetics and the safety evaluation of drugs. In the present paper we have studied an in vivo approach to the direct collection of human bile in the intestine during the intestinal absorption phase in healthy subjects.

Rosuvastatin (bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid [calcium salt]], molecular weight 1001.14 g/mol (AstraZeneca, 2003)) is a statin and reduces blood cholesterol by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co A) reductase in the hepatocyte. To reduce the systemic effects of statins, a high liver extraction, enterohepatic circulation and a low degree of metabolism are considered to be preferable drug properties and rat studies have shown that rosuvastatin is selectively distributed into the liver (Nezasa et al., 2002). The absolute oral bioavailability and hepatic extraction is estimated to be 20.1% and 63%, respectively, despite a low degree of metabolism both in vitro and in vivo (Fujino et al., 2004, Martin et al., 2003b, Martin et al., 2003d). After oral administration of [14C]rosuvastatin, 93% of the dose was recovered in the faeces, mainly in the form of the parent compound (76.8%), and the remaining 10% of the dose was recovered in the urine (Martin et al., 2003d). Previously published studies showing multiple peaks in the plasma profiles have suggested that rosuvastatin undergoes enterohepatic circulation, but the in vivo biliary secretion of rosuvastatin has not been previously investigated in humans (Martin et al., 2003b, Martin et al., 2003c).

Drug–drug interaction studies have shown a significant increase in the bioavailability, but not in the plasma half-life of rosuvastatin after co-administration with gemfibrozil and cyclosporine (Schneck et al., 2004, Simonson et al., 2004). However, modest to no interaction have been shown in vivo after co-administration with fenofibric acid (CYP3A4) (Martin et al., 2003a), erythromycin (CYP3A4) (Cooper et al., 2003a), digoxin (ABCB1) (Martin et al., 2002b), itraconazole (CYP3A4, ABCB1) (Cooper et al., 2003c), ketoconazole (CYP3A4, ABCB1) (Cooper et al., 2003b) and fluconazole (CYP2C9, CYP2C19) (Cooper et al., 2002). It has been suggested that the interactions with gemfibrozil and cyclosporine might be mediated by inhibiting OATP1B1 (OATP-C) that is considered to be the main uptake mechanism for rosuvastatin into the liver (Brown et al., 2001, Schneck et al., 2004, Simonson et al., 2004). Further studies have also indicated that rosuvastatin is a substrate for ABCG2 (BCRP, Km 14 μM) (AAPS meeting, 7–9 March, 2005). The more extensive effect of cyclosporine on the pharmacokinetics of rosuvastatin than that of gemfibrozil might be explained by dual inhibition by OATP1B1 mediated liver uptake and ABCG2 mediated biliary secretion by cyclosporine (Qadir et al., 2005, Schneck et al., 2004, Simonson et al., 2004). Taken together, the results emphasize the need to investigate biliary secretion of rosuvastatin during the absorption phase.

The main aim of this study was to investigate the feasibility of an intensive bile sampling method in humans and to characterize the bile secretion of rosuvastatin and bile acids during the absorption phase. In addition, we performed a qualitative investigation of the presence of any bile specific rosuvastatin metabolites.

Section snippets

Subjects and study design

The study included five male (subjects 2, 4, 6, 8 and 9) and five female (subjects 1, 3, 5, 7 and 10) volunteers, all of whom were deemed to be healthy by a physician; they were of normal weight and were between 21 and 38 years old (Martin et al., 2002a). The subjects had fasted overnight (at least 10 h) before the start of the experiment, with the exception of subject eight, who had breakfast on the morning of the study day. Subject six received intravenously administered glucose solution

Results

The Loc-I-Gut tube was successfully positioned in all ten subjects within approximately 1 h (range 20 min–2 h) (Fig. 1). However, subject nine terminated the experiment directly after drug administration and subject three terminated the experiment after 150 min owing to discomfort caused by the tube. The remaining eight subjects were able to successfully complete the study. The average bile flow was 0.52 ± 0.22 ml/min, but there was high intra-individual variability during the 4 h long sampling period (

Discussion

This technique has proven to be a feasible method for the investigation of the human biliary secretion of drugs, metabolites and endogenous compounds following intestinal administration of drugs. The method enables intensive sampling to be made of the bile in the distal duodenum/proximal jejunum, distal of papilla of Vater, during the absorption phase, i.e., the first 4 h of drug absorption and disposition. Unlike previously existing biliary secretion methods, this modified Loc-I-Gut technique

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