Interaction Of Rosuvastatin Research Articles

Novel Explanted Human Liver Model to Assess Hepatic Extraction, Biliary Excretion and Transporter Function.

Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can assess hepatic extraction, clearance, biliary excretion, and drug-drug interaction (DDI). Eleven livers were included in the study, seven with a cirrhotic and four with a noncirrhotic disease background. After explantation of the diseased liver, NMP was initiated. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin, and furosemide; OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with perpetrator drugs to study relevant DDIs. The explanted livers showed good viability and functionality during 360 minutes of NMP. Hepatic extraction ratios close to in vivo reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in maximum plasma concentration (Cmax ) of 11.50 and 2.89 times, respectively, compared with noncirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in noncirrhotic livers compared with cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion, and DDI. Gaining insight into pharmacokinetic profiles of OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds is a first step toward studying transporter functions in diseased livers.

Synthetic Characterization of Complexes of Rosuvastatin and Some ACE Inhibitors: Pharmacological Evaluation

Rosuvastatin is an anti-hypercholesterolemic agent with good anti-inflammatory and antinociceptive responses. The objective of present study was to assess the pharmacological effects of interaction of rosuvastatin with coprescribed ACE inhibitors. For this purpose complexes of Rosuvastatin with enalapril, captopril and lisinopril were synthesized and characterized. Their spectroscopic analyses suggest that hydrogen bonded complexation occurs between rosuvastatin and selected ACE inhibitors at their carboxylic (COOH) and hydroxyl OH sites. The anti-nociceptive effect of complexes was assessed by formalin induced nociception in mice, antiinflammatory effect was evaluated by carrageenan induced paw edema in rats. Neuropharmacological behaviors were also studied on mice. All the complexes of Rosuvastatin showed analgesic behavior in rats and mice. Anti-inflammatory activity of complexes is found insignificant. Enalapril complex keeps sedative activity while complexes with captopril and lisinopril contain anti-depressant behaviors. Results suggest that the interaction of rosuvastatin with ACE inhibitors have consumed the active reacting sites of Rosuvastatin for which its anti-inflammatory, analgesic and gross locomotor behaviors have been affected. So it is suggested that Rosuvastatin should not be co-administered with any of these ACE inhibitors.

Preparation, characterization and pharmacodynamic activity of supramolecular and colloidal systems of rosuvastatin–cyclodextrin complexes

In the present study influence of nature of selected cyclodextrins (CDs) and of methods of preparation of drug–CD complexes on the oral bioavailability, in vitro dissolution studies and pharmacodynamic activity of a sparingly water soluble drug rosuvastatin (RVS) was investigated. Phase solubility studies were conducted to find the interaction of RVS with β-CD and its derivatives, which indicated the formation of 1:1 stoichiometric inclusion complex. The apparent stability constant (K1:1) calculated from phase solubility diagram were in the rank order of β-CD < hydroxypropyl-β-cyclodextrin (HP-β-CD) < randomly methylated-β-cyclodextrin (RM-β-CD). Equimolar drug–CD solid complexes prepared by different methods were characterized by the Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). FTIR study demonstrated the presence of intermolecular hydrogen bonds and ordering of the molecule between RVS and CDs in inclusion complexes. DSC and XRD analysis confirmed formation of inclusion complex by freeze dried method with HP-β-CD and RM-β-CD. Aqueous solubility and dissolution studies indicated improved dissolution rates of prepared complexes in comparison with drug alone. Moreover, CD complexes demonstrated of significant improvement in reducing total cholesterol and triglycerides levels as compared to pure drug. However the in vivo results only partially agreed with those obtained from phase solubility studies.