英文版生物转化.ppt

* * * * * To represent the diversity of the CYP450 enzymes, a nomenclaturehas been created to identify different families and subfamilies. This nomenclature is based on the amino acid sequence of the protein and their assignment to different gene families (1, 2, 3, 4, etc.). * where Q is the hepatic blood flow (volume/time); Clint is the intrinsic hepatic clearance (volume/time); fB is the fraction of unbound drug in blood (no unit). Q: physiological parameter Clint: biochemical parameter fB: physiochemical or biopharmaceutical parameter CL: physiological (biopharmaceutical) parameter indicative of efficiency of removal processes (Organ) Clearance (Organ) Extraction Ratio (Organ) Availability Bioavailability Systemic Clearance iv dosing oral dosing If CLint Q (ie, fBClintQ), ∴ CL ∝ fBCLint Enzyme-limited Clearance or, Capacity-limited Clearance If CLint Q (ie, fBClint Q), ∴CL ∝ Q Flow-limited Clearance Enzyme-limited CL Flow-limited CL General Expressions ≈1 ≈1 (→0) (→0) ‘restrictive’ and ‘nonrestrictive’ clearance — to categorize drug substrates according to their clearance behavior in response to alterations in plasma protein binding ? Restrictive Clearance — applying to drugs that have low extraction ratios or intrinsic clearances ( fBCLint ) that are much lower than hepatic blood flow; in which case hepatic extraction is proportionately related to the equilibrium free fraction of drug in blood. ? Nonrestrictive Clearance — applying largely to drugs that have high extraction ratios (i.e., drugs with a high first-pass effect); specifically in cases when extraction ratio (E) exceeds the equilibrium free fraction in plasma. 5. The prediction of human clearance from hepatic microsomal metabolism data A high percentage of compounds aborted at various stages in the development process due to a varitey of reasons To optimized drug disposition properties Clearance Volume of Distribution Absorption Oral Bioavailability Half-life Dosing Regimen: Ho