The absorption of rosuvastatin was accelerated (C max was doubled, with T max change from 5 h to 0.75 h), whereas its AUC increased by only 1.18-fold when coadministered with telmisartan, although the cause of this phenomenon was not identified by the authors. reported increased pharmacokinetic (PK) exposure of rosuvastatin when coadministered with telmisartan. Rosuvastatin is commonly used in combination with telmisartan, an angiotensin II type-I receptor antagonist (ARB).
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Thus, multiple drug therapy has been widely practiced to treat problems including hypertension and dyslipidemia. It is also a substrate of efflux transporters such as the liver canalicular and intestinal breast cancer resistance protein (BCRP).Īmong patients with cardiovascular disease in a three-year retrospective study, 30.7% were found to have both hypertension and dyslipidemia, and 66.3% of patients with diabetes had concomitant hypertension and dyslipidemia. Rosuvastatin is extensively distributed into the liver, presumably because of active uptake by organic-anion transporting polypeptides (OATPs)1B1, OATP1B3, and OATP2B1, and by the sodium-dependent taurocholated cotransporting polypeptide (NTCP) transporters, despite its low passive diffusion into hepatocytes. Rosuvastatin is mainly excreted unchanged into bile, and less than 10% is metabolized to N-desmethyl rosuvastatin by CYP2C9. Following intravenous administration of rosuvastatin, clearance is predominantly nonrenal, with hepatic and renal routes of elimination accounting for 72% and 28% of total systemic clearance, respectively.
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The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin (Crestor) effectively reduces low-density lipoprotein cholesterol levels in dyslipidemic patients. This may be used as a clue for further physiologically based PK (PBPK) approaches to investigate the mechanism of rosuvastatin–telmisartan DDI. Thus, our model implies that telmisartan may influence the absorption process of rosuvastatin rather than its metabolic elimination. Notwithstanding the accelerated absorption, the relative bioavailability (BA) parameter estimate in the model demonstrated that the telmisartan-induced increase in BA was only about 20% and the clearance was not influenced by telmisartan at all in the final PK model. When telmisartan was coadministered, the zero-order absorption fraction of rosuvastatin had to be omitted from the model because the absorption was dramatically accelerated. The plasma concentration–time profile of rosuvastatin was best described by a two-compartment, first-order elimination model with simultaneous Erlang and zero-order absorption when given rosuvastatin alone. Rosuvastatin population PK models with or without telmisartan were developed using NONMEM (version 7.3).
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We used data from drug–drug interaction (DDI) studies of 74 healthy volunteers performed in three different institutions. The aim of this study was to explore which of the pharmacokinetic (PK) parameters of rosuvastatin are changed by telmisartan to cause such an interaction. The C max and AUC of rosuvastatin increase when it is coadministered with telmisartan.