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著者: アップロード:2017-09-07 閲読回数:
• Absorption ‐ Route of Drug Delivery– Where absorbed?• Distribution ‐ Where does the drug go, where does it need to go and what are the implications?
• Metabolism Metabolism ‐ This will occur and could impact several several variables variables.– Could be used to your advantage ‐ Prodrugs.• Excretion – How is the drug eliminated?
• Pharmacokinetics is concerned with the variation in drug concentration with time as a result of absorption, metabolism, distribution and excretion– Drug dose, route of administration, administration, rate and extent of absorption, absorption, distribution distribution rate (particularly to site of action) and rate of elimination.– Pharmacokinetics may be simply defined as what the body does to the drug.– Pharmacodynamics defined as what the drug does to the body.
• Pharmacokinetics including dosing via i.v., oral, subcutaneous, intraperitoneal or intramuscular routes
• Calculation of basic PK parameters
• Bioavailability following dosing by any of these routes
• Metabolism studies, including metabolite identification (mass spectral and/or after enzymatic incubations)
• Recovery of parent drug and/or metabolites in urine, faeces or bile
• Tissue distribution studies, including dosing with nonradiolabelled or radiolabelled (supplied by the Sponsor)versions of the investigational drug
• Metabolic stability screening or profiling due to Phase I (CYP450) or Phase II (glucuronidation / sulfonation) processes
• Studies conducted using cryopreserved hepatocytes (pooled human or male or female animal), microsomes or S9 as appropriate
• Identification of CYP450 isoforms responsible for metabolism using recombinant human CYPs
• Isolated perfused rat liver – TetraQ-ADME has many years experience with this model
• Caco-2 cell in vitro absorption studies
Drugs are specifically designed using ADME principles; however, chemicals for commercial use are not designed with any guidelines targeting ADME.
To be absorbed, a substance must cross one of the layers of cells that keeps “us” “in” and the rest of the world “out”: skin (including mucus membranes), lung, and the gastrointestinal (GI) tract. Most substances are absorbed by passive diffusion through membranes. A small number of biologically important atoms and molecules are actively taken up by cells. Examples include sodium, potassium, and calcium ions, amino acids, small sugars (mono- and di-saccarides). If your substance is very similar to one of these, there is an increased chance of cellular uptake. Solubility into membranes is the primary factor affecting absorption.
- Passive diffusion. Diffusion occurs through the lipid membrane from a high to low concentration (aka concentration gradient).
- Filtration. Diffusion occurs through aqueous pores, still from high to low concentration as a driving mechanism.
- Special transport. Transport is aided by a carrier molecule. Can move against the concentration gradient (low to high).
- Endocytosis. Transport takes the form of pinocytosis for liquids and phagocytosis for solids.
- Many times the mechanism of transport for a certain chemical is unknown, and so we must judge its potential toxicity using other variables (such as molecular weight, ionization (pKa), and octanol/water partition coefficient (logP)).