Biomaterial Database

Predicting drug-drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. 2010

Tatsuhiko Tachibana, and Motohiro Kato, and Junichi Takano, and Yuichi Sugiyama

Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.

Recently, interest has grown in drug-drug interactions (DDIs) involving the inhibition of intestinal CYP3A4, P-glycoprotein (P-gp), and other drug efflux transporters. The criteria for intestinal DDIs are described in the draft guidances of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Substrate drugs with small fraction absorbed (Fa) and/or low intestinal availability (Fg) as a result of intestinal efflux transport and metabolism are important as "victim" drugs because these substrates are likely to show considerable interactions. The susceptibility of a victim drug to intestinal interactions can be evaluated from its FaFg. In this review, methods for estimating the FaFg of substrate drugs are discussed. The nonlinear pharmacokinetics of substrate drugs caused by the saturation of intestinal CYP3A4/P-gp is also discussed. The methods for predicting intestinal DDIs caused by inhibitor drugs are then summarized. Because the prediction accuracy of intestinal DDIs also depends on the inhibition constant (Ki) estimated in in vitro studies, these in vitro methods of estimating Ki are also discussed. Standardized methods for predicting intestinal DDIs have not yet been established. Further studies are required to establish more accurate and standardized prediction methods.

UI	MeSH Term	Description	Entries
D007408	Intestinal Absorption	Uptake of substances through the lining of the INTESTINES.	Absorption, Intestinal
D007413	Intestinal Mucosa	Lining of the INTESTINES, consisting of an inner EPITHELIUM, a middle LAMINA PROPRIA, and an outer MUSCULARIS MUCOSAE. In the SMALL INTESTINE, the mucosa is characterized by a series of folds and abundance of absorptive cells (ENTEROCYTES) with MICROVILLI.	Intestinal Epithelium,Intestinal Glands,Epithelium, Intestinal,Gland, Intestinal,Glands, Intestinal,Intestinal Gland,Mucosa, Intestinal
D008954	Models, Biological	Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.	Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D010599	Pharmacokinetics	Dynamic and kinetic mechanisms of exogenous chemical DRUG LIBERATION; ABSORPTION; BIOLOGICAL TRANSPORT; TISSUE DISTRIBUTION; BIOTRANSFORMATION; elimination; and DRUG TOXICITY as a function of dosage, and rate of METABOLISM. LADMER, ADME and ADMET are abbreviations for liberation, absorption, distribution, metabolism, elimination, and toxicology.	ADME,ADME-Tox,ADMET,Absorption, Distribution, Metabolism, Elimination, and Toxicology,Absorption, Distribution, Metabolism, and Elimination,Drug Kinetics,Kinetics, Drug,LADMER,Liberation, Absorption, Distribution, Metabolism, Elimination, and Response
D004347	Drug Interactions	The action of a drug that may affect the activity, metabolism, or toxicity of another drug.	Drug Interaction,Interaction, Drug,Interactions, Drug
D004364	Pharmaceutical Preparations	Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form.	Drug,Drugs,Pharmaceutical,Pharmaceutical Preparation,Pharmaceutical Product,Pharmaceutic Preparations,Pharmaceutical Products,Pharmaceuticals,Preparations, Pharmaceutical,Preparation, Pharmaceutical,Preparations, Pharmaceutic,Product, Pharmaceutical,Products, Pharmaceutical
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284	Administration, Oral	The giving of drugs, chemicals, or other substances by mouth.	Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia