In Vitro to in Vivo Extrapolation and Physiologically Based Modeling of Cytochrome P450 Mediated Metabolism in Beagle Dog Gut Wall and Liver

Heikkinen, Aki T.; Fowler, Stephen; Gray, Lynn; Li, Jia; Peng, Ying; Yadava, Preeti; Railkar, Aruna; Parrott, Neil

doi:10.1021/mp300692k

Cited by 20 publications

(21 citation statements)

References 59 publications

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“…Finally, the provided information on protein abundance and total content ratios in the liver and along the human intestine may be useful to optimize existing in vitro-in vivo extrapolation of drug metabolism and transport in PBPK models, and, furthermore, to derive appropriate scaling factors for data generated in in vitro systems (e.g., transporter overexpressing cell lines and lipovesicles) or humanized animal models. 48…”

Section: Discussionmentioning

confidence: 99%

Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens

Droździk

Busch

Łapczuk

et al. 2019

Clin Pharma and Therapeutics

101

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Bioavailability of orally administered drugs is partly determined by function of drug transporters in the liver and intestine. Therefore, we explored adenosine triphosphate–binding cassette (ABC) and solute carriers family transporters expression (quantitative polymerase chain reaction) and protein abundance (liquid chromatography tandem mass spectrometry (LC‐MS/MS)) in human liver and duodenum, jejunum, ileum, and colon in paired tissue specimens from nine organ donors. The transporter proteins were detected in the liver (permeability‐glycoprotein (P‐gp), multidrug resistance protein (MRP)2, MRP3, breast cancer resistance protein (BCRP), organic anion‐transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic cation transporter (OCT)1, OCT3, organic anion transporter 2, Na+‐taurocholate cotransporting polypeptide, monocarboxylate transporter (MCT)1, and multidrug and toxin extrusion 1) and the intestine (P‐gp, multidrug‐resistance protein (MRP)2, MRP3, MRP4, BCRP, OATP2B1, OCT1, apical sodium–bile acid transporter (only ileum), MCT1, and peptide transporter (PEPT1)). Significantly higher hepatic gene expression and protein abundance of ABCC2/MRP2, SLC22A1/OCT1, and SLCO2B1/OATP2B1 were found, as compared to all intestinal segments. No correlations between hepatic and small intestinal protein levels were observed. These observations provide a description of drug transporters distribution without the impact of interindividual variability bias and may help in construction of superior physiologically based pharmacokinetic and humanized animal models.

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Section: Discussionmentioning

confidence: 99%

Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens

Droździk

Busch

Łapczuk

et al. 2019

Clin Pharma and Therapeutics

101

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“…The reason for this gap is that the BCS was developed based upon human digestive physiology, which can be vastly different from that observed in veterinary species. Given the similarity of therapeutic entities used in the dogs and humans, and because of the use of the dog as a preclinical species for human medicine (10), it would be of particular value to have an understanding of how the BCS criteria can be translated between human and canine gastrointestinal (GI) physiologies.…”

Section: Introductionmentioning

confidence: 99%

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

Papich

Martinez

2015

AAPS J

112

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Abstract. The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of Bwhat if^scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug's F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or paracellular transporters). Although there are limitations to the approach used in this study, the results of our assessment strongly suggest that the human BCS classification system requires substantial modification before it can be reliably applied to dogs.

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“…If a disconnect exists between observations and predictions in this class, hepatic non-CYP mediated and gut metabolism should be further investigated. This could be done at least qualitatively with in vitro experiments since the quantitative extrapolation to in vivo is challenging (32,33).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery

et al. 2016

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The generic GastroPlus ACAT model provided reasonable predictions especially for BCS class 1 compounds. For compounds of other classes, the model may be refined by obtaining more information on solubility and permeability in secondary assays. This increases confidence that such a model can be used in discovery projects to understand the parameters limiting absorption and extrapolate predictions across species. Also, when predictions disagree with the observations, the model can be updated to test hypotheses and understand oral absorption.

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In Vitro to in Vivo Extrapolation and Physiologically Based Modeling of Cytochrome P450 Mediated Metabolism in Beagle Dog Gut Wall and Liver

Cited by 20 publications

References 59 publications

Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens

Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

Evaluation of the GastroPlus™ Advanced Compartmental and Transit (ACAT) Model in Early Discovery

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