Biliary excretion of olmesartan, an anigotensin II receptor antagonist, in the rat

ABSTRACT:Hepatic uptake and biliary excretion of olmesartan, a new angiotensin II blocker, were investigated in vitro using human hepatocytes, cells expressing uptake transporters and canalicular membrane vesicles, and in vivo using Eisai hyperbilirubinemic rats (EHBR), inherited multidrug resistance-associated protein (mrp2)-deficient rats. The uptake by human hepatocytes reached saturation with a Michaelis constant (K m ) of 29.3 ؎ 9.9 M. Both Na ؉ -dependent and Na ؉ -independent uptake of olmesartan by human hepatocytes were observed. The uptake by Na ؉ -independent human liver-specific organic anion transporters OATP1B1 and OATP1B3 expressed in Xenopus laevis oocytes was also Olmesartan medoxomil (Benicar in United States; Olmetec in Europe and Japan) is a novel angiotensin II receptor antagonist available for treatment of hypertension. It is a prodrug that is rapidly and completely hydrolyzed in the gastrointestinal tract to a pharmacologically active form, olmesartan. Clinical pharmacokinetic data show that olmesartan is not further metabolized and that 60% of the dose was excreted into the feces via bile as olmesartan, with the remaining approximately 40% of the dose being excreted into the urine also as olmesartan ). This dual excretion route of olmesartan would decrease the risk of increased blood level of olmesartan caused by renal or hepatic impairment. In fact, clinical pharmacokinetic data show that the area under the concentration time curve (AUC 0 -24h ) of olmesartan in the patients with severe renal impairment (creatinine clearance Ͻ20 ml/min) increased by just 96% relative to that in healthy subjects. In addition, in the patients with moderate hepatic impairment, the AUC 0 -24h value of olmesartan increased by just 17% relative to that of healthy subjects (von Bergmann et al., 2001).The hydrophilic nature of olmesartan as indicated by log D at pH 7.0 (Ϫ1.2; in-house data) and a high ratio of the ionized form at pH 7.4 as indicated by the pKa value (4.3; in-house data) were considered to limit greatly permeation of olmesartan through the cell membrane by passive diffusion. Therefore, the high fecal excretion of olmesartan via biliary excretion observed in vivo in humans was thought to be a consequence of the basolateral uptake and biliary excretion of olmesartan mediated by transporters in a concerted manner. In the case of rats, a previous study reported that the biliary excretion of olmesartan is mediated by multidrug resistance-associated protein 2 (mrp2) based on low biliary excretion in Eisai hyperbilirubinemic rats (EHBR), which are inherited mrp2-deficient rats, compared with SpragueDawley rats (Takayanagi et al., 2005). However, the transporters involved in the hepatobiliary transport of olmesartan in humans have not been fully investigated yet. Na ϩ -dependent and Na ϩ -independent hepatic basolateral transport systems are known to be responsible for the clearance of various endogenous and exogenous substances from the systemic circulation (Meier, 1988;Tiribelli et al., 1990). As Na ϩ ...

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Oatp1b1, Oatp1b3, and Mrp2 Are Involved in Hepatobiliary Transport of Olmesartan, a Novel Angiotensin Ii Blocker

Nakagomi-Hagihara¹,

Nakai²,

Kawai³

et al. 2006

“…Because Bcrp protein expression increased during culture, in contrast to the decrease in Mrp2 and bile salt export pump expression (Li et al, 2010), intrinsic biliary clearance for rosuvastatin is relatively higher than that of other compounds in SCRH. Meanwhile, it was reported that Mrp2 mainly contributes to biliary secretion of pravastatin, angiotensin receptor blockers (valsartan and olmesartan), and ␤-lactam antibiotics (cefoperazone and cefpiramide) (Muraoka et al, 1995;Sasaki et al, 2004;Takayanagi et al, 2005;Yamashiro et al, 2006;Kato et al, 2008). Because the main contributor that excreted rosuvastatin into bile was different from that for the other compounds, a deviation of rosuvastatin from the correlation among these compounds would be observed.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes

Nakakariya

Ono²,

Amano³

et al. 2011

ABSTRACT:It has been reported that in vivo biliary clearance can be predicted using sandwich-cultured rat and human hepatocytes. The predicted apparent biliary clearance (CL bile, app ) from sandwichcultured rat hepatocytes (SCRH) based on medium concentrations correlates to in vivo CL bile, app based on plasma concentrations of angiotensin II receptor blockers (ARBs), HMG-CoA reductase inhibitors (statins), ␤-lactam antibiotics, and topotecan. However, the predicted biliary clearance from SCRH was 7-to 300-fold lower than in vivo biliary clearance. We speculated that the process of biliary excretion might not have been evaluated using sandwichcultured hepatocytes. To evaluate this issue, intrinsic biliary clearance (CL bile, int ) based on intracellular compound concentrations was evaluated to investigate the in vitro-in vivo correlation of this process among ARBs, statins, ␤-lactam antibiotics, and topotecan. Intrinsic biliary clearance in SCRH correlated to in vivo values obtained by constant intravenous infusion of six compounds, but not rosuvastatin and cefmetazole, to rats. Moreover, differences between SCRH and in vivo CL bile, int (0.7-6-fold) were much smaller than those of CL bile, app (7-300-fold). Therefore, in vivo CL bile, int is more accurately reflected using SCRH than CL bile, app . In conclusion, to predict in vivo biliary clearance more accurately, CL bile, int should be evaluated instead of CL bile, app between SCRH and in vivo.

“…When the same computational model was applied to 25 structurally diverse compounds whose rat biliary excretion data were published by different laboratories (Hirom et al, 1972b;Russell and Klaassen 1973;Fahrig et al, 1989;Monsarrat et al, 1990;Masuda et al, 1997;Hinchman et al, 1998;Payan et al, 1999;Song et al, 1999;Arimori et al, 2003;Chong et al, 2003;Funakoshi et al, 2003;Moriwaki et al, 2003;Kamath et al, 2005aKamath et al, ,b, 2008Kurihara et al, 2005;Takayanagi et al, 2005;Akashi et al, 2006;Beconi et al, 2007), the predicted and observed biliary excretion values were again very close for most compounds. The clear exceptions were cephradine and paclitaxel (Monsarrat et al, 1990;Moriwaki et al, 2003).…”

Section: Luo Et Almentioning

confidence: 99%

In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Luo¹,

Johnson²,

Hsueh³

et al. 2009

ABSTRACT:Evaluating biliary excretion, a major elimination pathway for many compounds, is important in drug discovery. The bile ductcannulated (BDC) rat model is commonly used to determine the percentage of dose excreted as intact parent into bile. However, a study using BDC rats is time-consuming and cost-ineffective. The present report describes a computational model that has been established to predict biliary excretion of intact parent in rats as a percentage of dose. The model was based on biliary excretion data of 50 Bristol-Myers Squibb Co. compounds with diverse chemical structures. The compounds were given intravenously at <10 mg/kg to BDC rats, and bile was collected for at least 8 h after dosing. Recoveries of intact parents in bile were determined by liquid chromatography with tandem mass spectrometry. Biliary excretion was found to have a fairly good correlation with polar surface area (r ‫؍‬ 0.76) and with free energy of aqueous solvation (⌬G solv aq ) (r ‫؍‬ ؊0.67). In addition, biliary excretion was also highly corrected with the presence of a carboxylic acid moiety in the test compounds (r ‫؍‬ 0.87). An equation to calculate biliary excretion in rats was then established based on physiochemical properties via a multiple linear regression. This model successfully predicted rat biliary excretion for 50 BMS compounds (r ‫؍‬ 0.94) and for 25 previously reported compounds (r ‫؍‬ 0.86) whose structures are markedly different from those of the 50 BMS compounds. Additional calculations were conducted to verify the reliability of this computation model.Biliary excretion is a major elimination pathway for many drugs and discovery compounds both in humans and in preclinical animals. For example, pravastatin and losoxantrone were found to be mainly eliminated as intact parent through biliary excretion in humans (Hatanaka 2000;Joshi et al., 2001). In rats, pravastatin and methotrexate were minimally metabolized and were primarily excreted intact into bile (Masuda et al., 1997;Kurihara et al., 2005). Extensive biliary excretion can be linked to a high clearance (Arimori et al., 2003), enterohepatic recirculation (Caldwell and Cline 1976;Rollins and Klaassen 1979), toxic gastrointestinal side effects (Kato et al., 2002), and potential drug-drug interactions (Luo et al., 2007). As a result, most lead discovery compounds are assessed for biliary excretion in selected preclinical animals early in the drug discovery and development process.Among the preclinical animal models, rats are the most commonly used model species for pharmacology, pharmacokinetics, and toxicology. The existing experimental models for determining rat biliary excretion include bile duct-cannulated rats and isolated perfused rat liver. However, these models are very time-consuming and costineffective because of complicated preparation of test models and difficulty in bile sample analyses.Undoubtedly, a computational model for predicting rat biliary excretion could significantly reduce laboratory efforts and, consequently, cost. Furthermore, a...