In Vitro and in Vivo Correlation of Hepatic Transporter Effects on Erythromycin Metabolism: Characterizing the Importance of Transporter-Enzyme Interplay

Lam, Justine L.; Okochi, Hideaki; Huang, Yong; Benet, Leslie Z.

doi:10.1124/dmd.106.009258

Cited by 77 publications

(92 citation statements)

References 28 publications

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“…A, the biotransformation of ximelagatran in the hepatocyte and possible transport mechanisms for ximelagatran and its metabolites. B, schematic picture of transport proteins in the hepatocyte that erythromycin inhibits or is a substrate for: P-gp (Takano et al, 1998;Polli et al, 2001), MRP1 (Terashi et al, 2000), organic anion transporter 2 (Kobayashi et al, 2005), OATP1B3, OATP1B1 , Oatp1a4, and Oatp1b2 (Lam et al, 2006). the f e,bile was 0.15, which is high when considering the poor passive permeability of melagatran (0.03 Ϯ 0.01 ⅐ 10 Ϫ6 cm/s) (Gustafsson et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Sjödin¹,

Fritsch²,

Eriksson³

et al. 2008

Drug Metab Dispos

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“…Thus, screens for both competitive and mechanism-based inhibition of key enzymes, for example, CYP3A4 (10), have been established and implemented in a high throughput fashion (11). In addition, the field of transporters localized in the plasma membrane and their role in drug uptake, efflux, and drug interactions has become a prominent area of investigation in recent years and is highly relevant to the pharmaceutical industry since it has become apparent that the interplay of drug-metabolizing enzymes and drug transporters can represent a critical determinant of drug disposition, drug interactions, and toxicity in animals and man (12). While initial interest focused on P-glycoprotein (13), current attention has broadened to encompass a wide spectrum of both organic anion and cation transporters that modulate the passage of many drug candidates across membrane barriers.…”

Section: The Past 20 Yearsmentioning

confidence: 99%

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

Baillie

2007

Chem. Res. Toxicol.

183

116

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The science of drug metabolism and pharmacokinetics (DMPK) has developed significantly over the past 20 years, and its functional role in today's pharmaceutical industry has matured to the point where DMPK has become an indispensable discipline in support of drug discovery and development. While contributions to the lead optimization phase of discovery efforts have been particularly noteworthy in helping to select only the best drug candidates for entry into development, it should be recognized that the scope of DMPK spans the continuum of discovery through clinical evaluation and even into the post-marketing phase; as such, the breadth of DMPK's involvement is almost unique in contemporary pharmaceutical research. This perspective summarizes notable advances in the field, many of which have been made possible by technological developments in areas such as molecular biology, genetics, and bioanalytical chemistry, and highlights the critical nature of key partnerships between Drug Metabolism, Medicinal Chemistry, and Safety Assessment groups in attempting to advance drug candidates with a low potential for causing adverse events in humans. Finally, some speculative predictions are made of the future role of DMPK in pharmaceutical research, where current advances in our mechanistic understanding of the molecular processes that control the absorption, disposition, metabolism, elimination, and toxicity of drugs and their biotransformation products will combine to further enhance the impact of DMPK in drug discovery and development.

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“…The activity of members of the solute carrier and ATP-binding cassette families of transporter proteins may provide a mechanistic explanation for the limited success achieved for some drugs using standard (hepatic microsomal) in vitro experiments to predict pharmacokinetic aspects of clearance and drug-drug interaction (DDI) potential (Lam et al, 2006;Soars et al, 2007;Parker and Houston, 2008). Although various theoretical scenarios involving hepatic transporters can be proposed, specific examples with experimental confirmation of an unequivocal nature have been largely restricted to the statins (Lau et al, 2006;Shitara et al, 2006;Paine et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

Brown¹,

Wilby²,

Alder³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Accurate assignment of the concentration of victim drug/inhibitor available at the enzyme active site, both in vivo and within an in vitro incubation, is an essential requirement in rationalizing and predicting drug-drug interactions. Inhibitor accumulation within the liver, whether as a result of active transport processes or intracellular binding, may best be accounted for using hepatocytes rather than hepatic microsomes to estimate in vitro inhibitory potency. The aims of this study were to compare K i values determined in rat liver microsomes and freshly isolated rat hepatocytes of four cytochrome P450 (P450) inhibitors (clarithromycin, enoxacin, nelfinavir, and saquinavir) with known hepatic transporter involvement and a range of uptake (cell/medium concentration ratios 20-3000) and clearance (10-1200 l/min/10 6 cells) properties.Inhibition studies were performed using two well established P450 probe substrates (theophylline and midazolam). Comparison of unbound K i values showed marked differences between the two in vitro systems for inhibition of metabolism. In two cases (clarithromycin and enoxacin, both low-clearance drugs), inhibitory potency in hepatocytes markedly exceeded that in microsomes (10-to 20-fold), and this result was consistent with their high cell/medium concentration ratios. For nelfinavir and saquinavir (high-clearance, extensively metabolized drugs), the opposite trend was seen in the K i values: despite very high cell/medium concentration ratios, stronger inhibition was evident within microsomal preparations. Hence, the consequences of hepatic accumulation resulting from uptake transporters vary according to the clearance of the inhibitor. This study demonstrates that transporter-enzyme interplay can result in differences in inhibitory potency between microsomes and hepatocytes and hence drug-drug interaction predictions that are not always intuitive.

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In Vitro and in Vivo Correlation of Hepatic Transporter Effects on Erythromycin Metabolism: Characterizing the Importance of Transporter-Enzyme Interplay

Cited by 77 publications

References 28 publications

Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

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