Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil

@article{Bergman2009EnterohepaticDO,
  title={Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil},
  author={E. Bergman and A. Lundahl and Patrik Fridblom and M. Hedeland and U. Bondesson and L. Knutson and H. Lennern{\"a}s},
  journal={Drug Metabolism and Disposition},
  year={2009},
  volume={37},
  pages={2349 - 2358}
}
The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively… Expand
The effect of acute administration of rifampicin and imatinib on the enterohepatic transport of rosuvastatin in vivo
TLDR
Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of ro SUVs, suggesting inhibition if sinusoidal transport. Expand
In Vivo Investigation in Pigs of Intestinal Absorption, Hepatobiliary Disposition, and Metabolism of the 5α-Reductase Inhibitor Finasteride and the Effects of Coadministered Ketoconazole
TLDR
It was found that the absorption rate from the intestine to the portal vein was rapid, and the product of the fraction absorbed and the fraction that escaped gut wall metabolism was high (fa · FG ∼1). Expand
Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs.
TLDR
It is demonstrated that CM transport of FEX in both liver and kidneys was inhibited by a single dose of verapamil, establishing that metabolism and CM uptake were important factors in the disposition of Fex in the liver. Expand
Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers
TLDR
The value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation is demonstrated, suggesting that the total plasma concentration of gemfibrozil needs to be above 20 μM to affect the disposition of rosuvastatin. Expand
The effects of lipiodol and cyclosporin A on the hepatobiliary disposition of doxorubicin in pigs.
TLDR
In conclusion, LIP did not directly interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX, and model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism ofDOX toDOXol. Expand
Investigation of hepatobiliary disposition of doxorubicin following intrahepatic delivery of different dosage forms.
TLDR
DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate, and results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues. Expand
Comparative Pharmacokinetics of Rosuvastatin in Male C57BL/6 Mice Following Single Intravenous and Oral Administration co-Administered With Herbal Bioenhancers
The purpose of this study was to investigate the potential pharmacokinetic interactions with herbal bioenhancers (such as piperine, gallic acid and cinnamic acid) and rosuvastatin (RSV) in healthyExpand
Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys
TLDR
The high levels of unchanged RSV recovered in urine and bile and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion, and further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition. Expand
The pharmacokinetics and hepatic disposition of repaglinide in pigs: mechanistic modeling of metabolism and transport.
TLDR
Both in vitro and in vivo results showed that carrier-mediated influx was important for the liver disposition of repaglinide in pigs, suggesting that both metabolism and carrier- mediated uptake are of significant importance for the Liver disposition. Expand
Role of enterohepatic recirculation in drug disposition: cooperation and complications
TLDR
Critically appraise the mechanisms of bile formation, factors affecting biliary drug elimination, methods to estimate biliary excretion of drugs, EHC, multiple peak phenomenon and its modeling. Expand
...
1
2
3
4
...

References

SHOWING 1-10 OF 44 REFERENCES
FIRST-PASS EFFECTS OF VERAPAMIL ON THE INTESTINAL ABSORPTION AND LIVER DISPOSITION OF FEXOFENADINE IN THE PORCINE MODEL
TLDR
A combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver, and the EH values for both verAPamil and antipyrine were similar to the corresponding values in vivo in humans. Expand
Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs
TLDR
It is suggested that transporters located at the sinusoidal and/or canalicular membranes of hepatocytes determine the hepatic disposition of ximelagatran and its metabolites, and are likely to mediate the xIMelag atran-erythromycin pharmacokinetic interaction. Expand
Gemfibrozil and its glucuronide inhibit the hepatic uptake of pravastatin mediated by OATP1B1
TLDR
It is hypothesized that gemfibrozil and the main plasma metabolites, a glucuronide and a carboxylic acid metabolite, might inhibit the hepatic uptake of pravastatin and lead to the elevation of the plasma concentration of pavastatin by the concomitant use of gem-glu. Expand
Is there an effect of food on the biliary secretion of cyclosporine and three in vivo formed metabolites in a porcine model
TLDR
Investigation of the biliary secretion of cyclosporine and in vivo formed metabolites in pigs showed that there was no difference between the administration groups, except for the fraction of the absorbed dose that was excreted in bile was twice as high when CsA was administered together with lipids. Expand
Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver.
TLDR
The study demonstrates the importance of the liver in the formation, uptake, hydrolysis, and excretion of 1-O-gemfibrozil-beta-D-glucuronide. Expand
The effect of fluconazole on the pharmacokinetics of rosuvastatin
TLDR
The results support previous in-vitro findings that CYP 2C9 and CYP2C19 metabolism is not an important clearance mechanism for rosuvastatin. Expand
Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase.
  • E. Bergman, P. Forsell, +5 authors H. Lennernäs
  • Biology, Medicine
  • European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2006
TLDR
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. Expand
Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers.
TLDR
Given the absolute bioavailability and estimated absorption of rosuvastatin, this finding suggests that metabolism is a minor route of clearance for this agent. Expand
Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers.
TLDR
The modest absolute oral bioavailability and high hepatic extraction of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing, and are well tolerated in this small number of healthy male volunteers. Expand
Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability.
TLDR
It is concluded that tacrolimus is metabolized by cytochrome CYP3A enzymes in the small intestine, and drugs that interfere with the in vitro metabolism of tacolimus in the liver also inhibit its small intestinal metabolism. Expand
...
1
2
3
4
5
...