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Lecture 4

Lecture 4 Clinical Trials

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University of Toronto St. George
Pharmaceutical Chemistry

Lecture 4 PHC320 Clinical Trials Pharmacokinetics Pharmacodynamics and Drug metabolismConsiderations and potential biases in Lipinskis rulesPrePost 1997Criteria dependent onof Lipinski rules consideredPost 1983 most small molecule screening libraries follow Lipinskis rulesDrug metabolismBody regards drugs as foreign substances not produced naturally xenobioticsBody has goal of removing such xenobiotics from system by excretion in the urineThe kidney is set up to allow polar substances to escape in the urine so the body tries to chemically transform drugs into more polar structuresPhase 1 metabolism involves the conversion of nonpolar bonds eg CH bonds to more polar bonds eg COH bondsA key enzyme is the cytochrome P450 system which catalyzes this reaction in the liver 75 of total metabolismRHO2H2eROHHO22Oxidationreductionhydrolysis most common mode of detoxificationeg steroids hormones antidepressantsPhase 2 metabolism liver links the drug to still more polar molecules to render them easier to excreteoConjugation reactions methylation sulphation acetylation glutathioneSecondary assays preclinical ADMEPKAdsorption and metabolismL solubility stability permeabilityCaco2 cells derived from large intestine carcinomaOther approachesMDCKkidneyBBB methodsHepatocytesMicrosomesmainly cytochrome P450sIn vivo testing 12 years animal modelsADMEPK mostly animal models considerationsExpenseSufferingDont necessarily know targetmechanismResult may be difficult to interpretWorks in an in vivo systemSubmission to FDA IND investigational new drug
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