Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Tang, Cuyue; Prueksaritanont, Thomayant

doi:10.1007/s11095-010-0157-z

Cited by 53 publications

(47 citation statements)

References 94 publications

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“…Increasingly, investigators are leveraging a combination of in vitro and in vivo animal (e.g., humanized rodents and nonhuman primates) data to support IVIVE involving the inhibition of drug-metabolizing enzymes (e.g., cytochrome P450 3A4) and transporters (e.g., organic anion transporting polypeptide) (Tang and Prueksaritanont, 2010;Shen et al, 2013;Jaiswal et al, 2014). When successful, appropriately characterized and validated animal models can provide mechanistic insight, support modeling, and enable IVIVE exercises.…”

Section: Introductionmentioning

confidence: 99%

Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation

Shen

Liu

Jiang

et al. 2015

Drug Metabolism and Disposition

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Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC 50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC 50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 6 0.38, 0.17 6 0.04, and 0.25 6 0.04 mM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 6 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitroin vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey-enabled IVIVEs may inform human DDI risk assessment. IntroductionIt is widely appreciated that renal elimination of cations, drug, toxin, or endogenous metabolite related, is achieved not only by glomerular filtration but also by active transport processes that facilitate their tubular secretion and reabsorption. Indeed, the mechanisms governing the renal elimination of organic cations have been studied in detail, and the transporters facilitating their tubular uptake and extrusion have been identified (Okuda et al., 1996;Otsuka et al., 2005;Masuda et al., 2006).Secretion of organic cations in renal proximal tubules involves at least two distinct transporters, located in the basolateral and apical membranes of proximal tubule cells (Motohashi et al., 2002Masuda et al., 2006). Specifically, organic cations, like metformin (MFM), 1-methyl-4-phenylpyridinium (MPP + ), tetraethylammonium (TEA), and cimetidine (CMD), are taken up from the circulation by organic cation transporter 2 (OCT2) expressed on the basolateral domain of renal proximal tubular cells. In turn, uptake is followed by efflux into the tubular fluid by multidrug and toxin extrusion protein (MATE) 1 and MATE2K expressed on the apical domain of the same cells. Therefore, OCT2 and MATEs function coordinately to mediate vectorial transport of certain cationic drugs, from blood to tubular fluid, which represents the tubular secretion clearance component of total renal clearance. Perturbation of c...

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Section: Introductionmentioning

confidence: 99%

Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation

Shen

Liu

Jiang

et al. 2015

Drug Metabolism and Disposition

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“…In this regard, the cynomolgus monkey has been used increasingly as a model to support the characterization of drug disposition prior to detailed human studies and the conduct of mechanistic (DDI) studies (Akabane et al, 2010;Tang and Prueksaritanont, 2010). Moreover, when compared with other species, there is high sequence identity between numerous cynomolgus monkey and human drugmetabolizing enzymes and transporters (Tahara et al, 2005;Yasunaga et al, 2008;Iwasaki and Uno, 2009).…”

Section: Introductionmentioning

confidence: 99%

Cynomolgus Monkey as a Potential Model to Assess Drug Interactions Involving Hepatic Organic Anion Transporting Polypeptides: In Vitro, In Vivo, and In Vitro-to-In Vivo Extrapolation

Shen

Yang

Mintier

et al. 2013

J Pharmacol Exp Ther

116

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Organic anion-transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug-drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17b-D-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC 50 values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV K m and RIF IC 50 ) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro-in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting. IntroductionDrug-drug interactions (DDIs) have often been attributed to cytochrome P450 (P450) enzymes because of their prominent role in the metabolic clearance of drugs (Vuppugalla et al., 2010). More recently, however, attention has turned to active transport processes in different organs and the close interplay between drug transport and metabolism at the cellular level. In particular, organic anion-transporting polypeptides (OATPs) are known to mediate the active uptake of numerous drugs into hepatocytes and hence govern their overall clearance, pharmacokinetic profile, and liver-toplasma ratio (Giacomini et al., 2010;Fenner et al., 2012;Yoshida et al., 2012).OATPs can also serve as the loci of important DDIs leading to changes in systemic and local drug concentrations, possibly resulting in altered efficacy and enhanced toxicity (Giacomini et al., 2010;Yoshida et al., 2012). For example, cyclosporine A (CsA) increases the area under the concentration-time curve (AUC) (∼15-fold) and C max (∼14-fold) of atorvastatin in s This article has supplemental material available at jpet.aspetjournals.org.ABBREVIATIONS: AUC, area under the concentration-time curve; CCK-8, cholecystokinin octapeptide; CI, confidence interval; cOATP, cynomolgus organic anion-transporting polypeptide; CsA, cyclosporine A; DDI, drug-drug inter...

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“…Although the zebrafish is gaining popularity as an animal model, the animals used most commonly in drug testing are genetically-modified mice, rats, dogs, and nonhuman primates [68]. Animals should be chosen on the basis of the physiological and biochemical similarities between the animal model and humans and the underlying mechanisms of drug absorption, distribution, metabolism, and excretion in the animal [69]. There are a number of examples of established animal models used for particular diseases (Table 2) [64].…”

Section: Choosing a Model Animalmentioning

confidence: 99%

In vivo Studies for Drug Development via Oral Delivery: Challenges, Animal Models and Techniques

Brake¹,

Gumireddy²,

Tiwari³

et al. 2017

Pharm Anal Acta

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Drug discovery and development involves a complex iterative process of new molecules synthesis, formulations, and in vitro analysis, followed by biochemical and cellular assays, with final validation in animal models, and ultimately in humans. The purpose of this article is to present a concise overview of the rationale and challenges for performing in vivo studies, the types of animal models, and modern in vivo research techniques for oral drug delivery.

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Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Cited by 53 publications

References 94 publications

Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation

Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation

Cynomolgus Monkey as a Potential Model to Assess Drug Interactions Involving Hepatic Organic Anion Transporting Polypeptides: In Vitro, In Vivo, and In Vitro-to-In Vivo Extrapolation

In vivo Studies for Drug Development via Oral Delivery: Challenges, Animal Models and Techniques

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