Page 5Lipophilic Natureallows• Passage through biochemical membranes• Access to the site of production• BUT it hinders excretion.• Lipophilic nature must be converted tohydropilic nature so it can be easilyexcreted
Page 6Metabolism• The metabolism of drugs and otherxenobiotics into more hydrophilicmetabolites is essential for theelimination of these compounds fromthe body and termination of theirbiological activity.• Chemical reactions include oxidation,reduction, hydrolysis, hydration,conjugation, condensation andisomeriztion.
Page 7Biotransformation• Generates more polar (water soluble),inactive metabolites• Readily excreted from body• Metabolites may still have potentbiological activity (or may have toxicproperties)• Generally applicable to metabolism ofall xenobiotics as well as endogenouscompounds such as steroids, vitaminsand fatty acids
Page 8Site of Biotransformation• Enzymatic in nature.• Enzyme systems involved are localized inliver.• Every tissue has some metabolic activity• Other organs with significant metaboliccapacity are GI tract, kidneys and lungs.
Page 9Endoplasmic Reticulum(microsomal) and Cytosol• With respect to drug metabolizing reactions,two sub cellular organelles are quantitativelythe most important: the endoplasmicreticulum and the cytosol.• The phase I oxidative enzymes are almostexclusively localized in the endoplasmicreticulum.• Phase II enzymes are located predominantlyin the cytosol.
Page 10Phase I and Phase IIMetabolism• Phase I– functionalization reactions (nonsynthetic)• Phase II– conjugation reactions (synthetic)• Phase III– elimination reactions (excretion in bile)
Page 11Phase I Metabolism(Includes oxidation, reduction, hydrolysis, andhydration and isomerization (plus rarer misc.)isomerization)• Many drugs undergo a number of thesereactions• Main function of Phase I metabolism is toprepare the compound for phase IImetabolism• Mixed function enzyme system found inmicrosomes of many cells (esp. liver, kidney,lungs, intestine) performs many differentfunctionalization reactions
Page 12Phase I• Converts the parent drug to a morepolar metabolites by introducing orunmasking a functional group (-OH,-NH2 ,-SH).• Usually results in loss ofpharmacological activity• Sometimes may be equally or moreactive than parent
Page 13Cytochrome P450Monooxygenase System• Superfamily of heme containing proteins• Involved in metabolism of diverseendogenous and exogenous compounds– Drugs– Environmental chemicals– Other xenobiotics
Page 14Prodrug• Pharmacologically inactive• Converted rapidly to active metabolites(usually hydrolysis of ester or amidebond)• Maximizes the amount of activemetabolites that reaches site of action
Page 15Cytochrome P450Nomenclature and MultipleForms• ~1000 currently known cytochrome P450s,about 50 active in humans• Basis of nomenclature system is divergentevolution – sequence similarity betweenthe cytochrome P450s
Page 17• categorized into 17 families (CYPs)– sequences > 40% identical– identified by Arabic number, CYP1, CYP2• further into subfamilies– sequences >55% identical– identified by a letter, CYP1A, CYP2D• may have different, individual isoforms– identified by another Arabic number, CYP2D6,CYP3A4
Page 18Phase I Metabolism SummaryVirtually every possible chemical reaction that acompound can undergo can be catalyzed by thedrug metabolizing enzyme systems• The final product usually contains a chemicalreactive functional group OH, NH2, SH, COOH.• This functional group can be acted upon by thephase II or conjugative enzymes.• Main function of Phase I metabolism is toprepare the compound for phase II metabolism,not excretion.
Page 19Phase II (conjugation reactions)• Subsequent reaction in which a covalentlinkage is formed between a functionalgroup on the parent compound or Phase Imetabolite and an endogenous substratesuch as glucuronic acid, sulfate, acetate,or an amino acid• Highly polar – rapidly excreted in urineand feces• Usually inactive - notable exception ismorphine 6-glucuronide
Page 20Phase II Metabolism• Phase II is usually the true detoxificationof drugs• Occurs mostly in cytosol• Gives products that are generally watersoluble and easily excreted• Includes sugar conjugation, sulfation,methylation, acetylation, amino acidconjugation, glutathione conjugation
Page 21Factors affecting DrugMetabolism• Environmental DeterminantsInductionInhibition• Disease Factors• Age and Sex• Genetic Variation
Page 22Environmental Determinants• Activity of most drug metabolizing enzymescan be modulated by exposure to certainexogenous compounds– Drugs– Dietary micronutrient (food additives,nutritional or preservative)– Environmental factors (pesticides,industrial chemicals)• Can be in the form of induction or inhibition• Contributes to interindividual variability in themetabolism of many drugs
Page 23Induction of Drug Metabolism• Enzyme induction is the process by whichexposure to certain substrates (e.g., drugs,environmental pollutants) results inaccelerated biotransformation with acorresponding reduction in unmetabolizeddrug.(some substance stimulates the synthesisof the enzyme and the metaboliccapacity is increased -drug getsmetabolized faster)
Page 24Induction of Drug Metabolism• Many currently used drugs are well known toinduce their own metabolism or themetabolism of other drugs. Some examplesare the anticonvulsant medicationsphenobarbital and carbamazepine, and evenSt. John’s Wort.• Cigarette smoking can cause increasedelimination of theophylline and othercompounds.
Page 25Consequences of Induction• Increased rate of metabolism• Decrease in drug plasmaconcentration• Reduced bioavailability• If metabolite is active or reactive,increased drug effects or toxicity
Page 26Inhibition of Drug Metabolism• Drug metabolism is an enzymaticprocess can be subjected to inhibition.• Drugs and other substances can inhibit themetabolism of other drugs.
Page 27Some types of inhibition• Competition between substrates for enzyme activesite– Competitive inhibition– Destruction of preexisting enzymes– Interference with enzyme synthesis– Affinity for binding site (drug with high affinity for anenzyme will slow the metabolism of any low affinitydrug)• Irreversible inactivation of enzyme –– Complex with heme iron of CYP450 (cimetidine,ketoconazole)– Destruction of heme group (secobarbital)• Depletion of cofactors such as NADP for phase IIenzymes
Page 28Consequences of Inhibition• Increase in the plasmaconcentration of parent drug• Reduction in metaboliteconcentration• Exaggerated and prolongedpharmacological effects• Increased likelihood of drug-induced toxicity
Page 29Disease Factors• Liver Disease – Cirrhosis, Alcoholic liverdisease, jaundice, carcinoma– Major location of drug metabolizing enzymes– Disfunction can lead to impaired drug metabolism-decreased enzyme activity– Results in exaggerated pharmacologicalresponses and adverse effects• Cardiac failure causes decreased blood flowto the liver• Hormonal diseases, infections andinflammation can change drug metabolizingcapacity
Page 30Age• Newborns and infants – metabolize drugsrelatively efficiently but at a rate generallyslower than adults• Full maturity appears in second decade oflife• Slow decline in function associated withaging
Page 32Sex• Responsiveness to certain drugs isdifferent for men and women• Pregnancy – induction of certain drugmetabolizing enzymes occurs in secondand third trimester• Hormonal changes during developmenthave a profound effect on drugmetabolism
Page 33Genetic Variation• Wide variability in the response to drugsbetween individuals• Consequences of such variation may betherapeutic failure or an adverse drugreaction• Genetic diversity is the rule rather thanthe exception with all proteins, includingdrug metabolizing enzymes
Page 34• Inheritance leads to subpopulations(genetic polymorphisms) with different drugmetabolizing abilitieslack of activityreduction in catalytic abilityenhanced activity• Frequency of the polymorphism oftenvaries according to the ethnic ancestry ofthe individual
Page 35• CYP2D6 is extensively studied, the gene forCYP2D6 is highly polymorphic• It’s expression leads to 3 phenotypes (phenotypeis the expression of genetic make-up)Extensive metabolizers (EMs) have functionalenzyme activityIntermediate metabolizers (IMs) have diminishedenzyme activityPoor metabolizers (PMs) have little or no activity• 5-10% of Caucasians and 1-2% of Asiansexhibit the PM phenotype
Page 36• Remarkable interindividual variation inpharmacological effect of the drug