First-Pass Effects of Verapamil on the Intestinal Absorption and Liver Disposition of Fexofenadine in the Porcine Model

Petri, Niclas; Bergman, Ebba; Forsell, Patrik; Hedeland, Mikael; Bondesson, Ulf; Knutson, Lars; Lennernäs, Hans

doi:10.1124/dmd.105.008409

Cited by 40 publications

(45 citation statements)

References 39 publications

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“…The drugs were given in solution at room temperature as single-bolus doses into the proximal jejunum via a Loc-I-Gut perfusion tube (Synectics Medical, Stockholm, Sweden). This tube has been designed to allow simultaneous administration of drugs, intestinal perfusion, and sampling of biliary fluid in humans and large mammals (Knutson et al, 1989;Lennernas et al, 1992;Petri et al, 2006). Ximelagatran (AstraZeneca R&D, Mölndal, Sweden) was dissolved in acidified isotonic sodium chloride (at pH 4 for stability reasons) to a final concentration of 4.44 mg/ml (45-ml dose).…”

Section: Methodsmentioning

confidence: 99%

“…Second, the expression and activity of the major enzymes responsible for drug biotransformation are comparable with those in humans, thus making the pig a useful model for metabolic studies (Anzenbacher et al, 1998;Zuber et al, 2002). Less is known about the expression of transport proteins in pigs, although the pharmacokinetic properties of drugs known to be actively transported in humans (e.g., cyclosporine, digoxin, fexofenadine, verapamil, danazol) are similar (Petri et al, 2006;Tannergren et al, 2006;Persson et al, 2008). The possible use of porcine proximal tubular cells and brain capillary endothelial cells for mimicking drug transport in the human kidney and blood-brain barrier, respectively, is under investigation (Eisenblätter and Galla, 2002; Török et al, 2003;Schlatter et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…In both PI and PII, a prewarmed (37°C) phosphate buffer at pH 6.5 and 290 mOsm/kg osmolality was pumped through the intestinal segment at a flow rate of 2 ml/min using a syringe pump (model 355; Sage Instruments, Orion Research Inc., Cambridge, MA). The phosphate buffer (5.4 mM KCl, 48 mM NaCl, 10 mM D-glucose, 63 mM NaH 2 PO 4 , 34 mM Na 2 HPO 4 , 1.0 g/l polyethylene glycol 4000, and 35 mM mannitol) and flow rate have previously been used and validated in several in vivo perfusion studies (e.g., Lennernas et al, 1992;Petri et al, 2006). In this study, 0.2 mg/ml phenol red (SigmaAldrich, Stockholm, Sweden) was used as a nonabsorbable volume marker (Sutton et al, 2001).…”

mentioning

confidence: 99%

“…Urine and gastric fluid were removed by catheters inserted in the urinary bladder and stomach, respectively. An incision was made in the duodenum to enable insertion of the Loc-I-Gut perfusion tube (Synetics Medical, Stockholm, Sweden), which was positioned in the proximal jejunum (Knutson et al, 1989;Lennernas et al, 1992;Petri et al, 2006). Once in place, the two balloons attached to the Loc-I-Gut tube were inflated to create a 10-cm-long intestinal segment.…”

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confidence: 99%

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Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Sjödin¹,

Fritsch²,

Eriksson³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The direct thrombin inhibitor melagatran is formed from ximelagatran via two intermediate metabolites, OH-melagatran and ethylmelagatran. The biotransformation of ximelagatran does not involve cytochrome P450 isoenzymes, and it has been suggested that a reported interaction with erythromycin may instead be mediated by transport proteins. A pig model that simultaneously enables bile collection, sampling from three blood vessels and perfusion of a jejunal segment, was used to investigate the biotransformation of ximelagatran and the effect of erythromycin on the intestinal and hepatobiliary transport of ximelagatran and its metabolites. The pigs received enteral ximelagatran (n ‫؍‬ 6), enteral ximelagatran together with erythromycin (n ‫؍‬ 6), i.v. ximelagatran (n ‫؍‬ 4), or i.v. melagatran (n ‫؍‬ 4). The plasma exposure of the intermediates was found to depend on the route of ximelagatran administration. Erythromycin increased the area under the plasma concentration-time curve (AUC) of melagatran by 45% and reduced its biliary clearance from 3.0 ؎ 1.3 to 1.5 ؎ 1.1 ml/min/kg. Extensive biliary exposure of melagatran and ethylmelagatran, mediated by active transport, was evident from the 100-and 1000-fold greater AUC, respectively, in bile than in plasma. Intestinal efflux transporters seemed to be of minor importance for the disposition of ximelagatran and its metabolites considering the high estimated f abs of ximelagatran (80 ؎ 20%) and the negligible amount of the compounds excreted in the perfused intestinal segment. These findings suggest 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 ximelagatran-erythromycin pharmacokinetic interaction.Ximelagatran was the first oral direct thrombin inhibitor to reach the market. As an oral anticoagulant, it had the potential to become an alternative to warfarin and other vitamin K antagonists; however, because of safety concerns involving hepatotoxicity, ximelagatran was withdrawn in 2006. Warfarin currently has an important role in the prevention and treatment of thromboembolic events but is unfortunately also associated with a variable pharmacokinetic and pharmacodynamic response, delayed onset and offset of action, numerous drug-drug interactions, and serious safety issues (Hawkins, 2004;Greenblatt and von Moltke, 2005). The narrow therapeutic index of warfarin and the many sources of variability require monitoring of the anticoagulant effect to maintain blood levels within the therapeutic range. Because of these difficulties and the severe consequences of thrombosis, it is clear that there is a need for new oral anticoagulants. Ximelagatran was developed to improve the low and highly variable bioavailability of the reversible, direct thrombin inhibitor melagatran (Gustafsson et al., 2001). The hydrophilic carboxylic acid and amidine functions of melagatran were protected by introducing an ethylester residue and the less ...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Sjödin¹,

Fritsch²,

Eriksson³

et al. 2008

Drug Metab Dispos

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“…2) (Petri et al, 2006;Sjödin et al, 2008). Complementary in vitro depletion experiments in pig liver microsomes were also performed to investigate the potential effect of ketoconazole on the metabolism of the active compound in pigs.…”

Section: Introductionmentioning

confidence: 99%

Effects of Ketoconazole on the In Vivo Biotransformation and Hepatobiliary Transport of the Thrombin Inhibitor AZD0837 in Pigs

Matsson¹,

Palm²,

Eriksson³

et al. 2010

Drug Metab Dispos

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To investigate the biotransformation of AZD0837 and the effect of ketoconazole on this process, we used an experimental model in pigs that allows repeated sampling from three blood vessels, the bile duct, and a perfused intestinal segment. The pigs received AZD0837 (500 mg) given enterally either alone (n ‫؍‬ 5) or together with single-dose ketoconazole (600 mg) (n ‫؍‬ 6). The prodrug (n ‫؍‬ 2) and its active metabolite (n ‫؍‬ 2) were also administered intravenously to provide reference doses. The plasma data revealed considerable interindividual variation in the exposure of the prodrug, intermediate metabolite, and active metabolite. However, AR-H067637 was detected at very high concentrations in the bile with low variability (Ae bile ‫؍‬ 53 ؎ 6% of the enteral dose), showing that the compound had indeed been formed in all of the animals and efficiently transported into the bile canaliculi. Concomitant dosing with ketoconazole increased the area under the plasma concentration-time curve for AZD0837 (by 99%) and for AR-H067637 (by 51%). The effect on the prodrug most likely arose from inhibited CYP3A-mediated metabolism. Reduced metabolism also seemed to explain the increased plasma exposure of the active compound because ketoconazole prolonged the terminal half-life with no apparent effect on the extensive biliary excretion and biliary clearance. These in vivo results were supported by in vitro depletion experiments for AR-H067637 in pig liver microsomes with and without the addition of ketoconazole.

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Comparative Pharmacokinetics Studies of Immediate- and Modified-Release Formulations of Glipizide in Pigs and Dogs

Kulkarni

Yumibe

Wang

et al. 2012

Journal of Pharmaceutical Sciences

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First-Pass Effects of Verapamil on the Intestinal Absorption and Liver Disposition of Fexofenadine in the Porcine Model

Cited by 40 publications

References 39 publications

Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Effects of Ketoconazole on the In Vivo Biotransformation and Hepatobiliary Transport of the Thrombin Inhibitor AZD0837 in Pigs

Comparative Pharmacokinetics Studies of Immediate- and Modified-Release Formulations of Glipizide in Pigs and Dogs

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