Drug Metabolism and EliminationDrug MetabolismExamples of more active metabolitesDifferent Metabolites: 1 More active, 1 More ToxicPhases of Drug MetabolismDrug Metabolism - Phase I & II SLIDE #32PowerPoint PresentationSlide 8Drug Metabolism - Phase IDrug Metabolism - OxidationSlide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Drug Metabolism - ReductionSlide 21Drug Metabolism - Phase IDrug Metabolism - Phase IIDrug Metabolism - GlucuronidationSlide 25Slide 26Slide 27Slide 28Drug Metabolism - SulfationDrug Metabolism - AcylationDrug Metabolism - Other conjugationsDrug Metabolism - Phase I & IIDrug Action: Receptor TheorySlide 34BIMM118Drug Metabolism and Elimination•Elimination of drugs occurs primarily through renal mechanism–Secretion into bile also possible, but allows for re-absorption in the intestine•Secretion into the urine requires ionized or hydrophilic molecules, but:–Most drugs are not small molecules that are highly ionized at body pH–Most drugs are poorly ionized and lipophilic=> This decreases renal excretion and facilitates renal tubular reabsorption–Many drugs are highly protein bound, and therefore not efficiently filtered in the kidney–Most drugs would have a long duration of action if termination of their effects depended only on renal excretion•Inactivation versus elimination of the active drugSolution: Drug MetabolismBIMM118Drug Metabolism•Why is drug metabolism so important? Elimination of drugs and chemicals by the kidney is often compromised because the drug/chemical is too nonpolar, lipophilic and readily “reabsorbed” from tubular fluid. Metabolism can convert the drug to a more hydrophilic compound reducing reabsorption. •Most metabolic products are less pharmacologically activeImportant exceptions:•Where the metabolite is more active - 3 examples(Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) --> Erythromycin, enaliprilat -> enalapril, codeine)•Where the metabolite is toxic (acetaminophen)•Where the metabolite is carcinogenic•Close relationship between the biotransformation of drugs and normal biochemical processes occurring in the body:–Metabolism of drugs involves many pathways associated with the synthesis of endogenous substrates such as steroid hormones, cholesterol and bile acids –Many of the enzymes involved in drug metabolism are principally designed for the metabolism of endogenous compounds–These enzymes metabolize drugs only because the drugs resemble the natural compoundBIMM118Examples of more active metabolitesErythromycin – gram+ antibiotic; pH sensitive (enteric coating), nonpolar, esterified (succinic acid, proprionic acid); converted by cell esterasesEnaliprilat - ACE-Inhibitor; prodrug; esterase converts to Enalapril (active)Codeine – O-demethylation to morphine – more active analgesic than codeine; CYP2D6 metabolic enzyme; deficient in 10% caucasians, 2% in asians; reduced analgesia for same dosageBIMM118Different Metabolites: 1 More active, 1 More ToxicPhenacetin: 1887, analgesic, antipyretic, negative inotropic.Present in APC headache mix: aspirin+phenacetin+caffeineUse today: “cutting” cocaine, adulterant; chronic use leads to renal papillary necrosis due to metabolitesEthyl ester de-ethylation to acetaminophen (CYP2A13, CYP1A2)Acetaminophen more potent than phenacetinPhenacetin & acetaminophen conjugated with glucuronic acid or sulfate for eliminationPhenacetic metabolized by monooxygenase hydroxylation to toxic metabolites – NAPQI = N-acetyl-(1,4) benzoquinone imine and epoxidesAcetaminophen also conjugated and hydroxylated (CYP2E1, CYP2A6, CYP1A2)Hydroxylation leads to toxic metabolite imine and epoxideDetoxification: conjugation with Hepatic cell glutathione (GSH)If Overdose – deplete hepatic GSH; metabolites mitochondrial dysfunction, oxidative damage to proteins, liver cell necrosis and hepatic failureTherapy: N-acetyl cysteine or methionineBIMM118Phases of Drug Metabolism•Phase I Reactions–Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.)–Often these metabolites are rendered inactive by the conversion–The reaction product may be sufficiently polar to be excreted readily•Phase II Reactions–Conjugation with endogenous substrate to further increase aqueous solubility–Conjugation with glucoronide, sulfate, acetate, amino acid–Phase I usually precedes phase II reactionsLiver is principal site of drug metabolism:–Other sites include the gut, lungs, skin and kidneys–For orally administered compounds, there is the “First Pass Effect”•Intestinal metabolism•Liver metabolism•Enterohepatic recycling•Gut microorganisms - glucuronidasesBIMM118Drug Metabolism - Phase I & II SLIDE #32Phase I and II - Summary:•Products are generally more water soluble•These reactions products are ready for (renal) excretion•There are many complementary, sequential and competing pathways•Phase I and Phase II metabolism are a coupled interactive system interfacing with endogenous metabolic pathwaysBIMM118BIMM118Drug MetabolismA. Hydrophilic drugs absorbed in GI tract, pass through liver, get excreted by kidney.B. Lipophilic drug without metabolism, absorbed into blood, may get excreted into tubular fluid in kidney but reabsorbed – no elimination.C. Lipophilic drug slowly metabolized by liver enzymes; hydrophilic metabolite only one eliminated, unchanged drug recirculates.D. Lipophilic drug rapidly metabolized by liver enzymes, nearly complete elimination by kidney.A BCDBIMM118Drug Metabolism - Phase I•Phase I Reactions–Oxidation–Reduction–Hydrolytic cleavage–Alkylation (Methylation)–Dealkylation–Ring cyclization–N-carboxylation–Dimerization–Transamidation–Isomerization–DecarboxylationBIMM118Drug Metabolism - OxidationTwo types of oxidation reactions:–Oxygen is incorporated into the drug molecule (e.g. hydroxylation, epoxidations, sulfoxidations)–Oxidation causes the loss of part of the drug molecule (e.g. oxidative deimination, dealkylation)Microsomal Mixed Function Oxidases (MFOs)•“Microsomes” form in vitro after cell homogenization and fractionation of ER–Rough ER microsomes are primarily associated with protein synthesis –Smooth ER microsomes contain a class of oxidative enzymes called •“Mixed Function Oxidases” or “Monooxygenases”–These enzymes require a reducing agent (NADPH)
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