1. Drug Biotransformation Elimination of the drugs

2. Drug Biotransformation Metabolism or biotransformation - complex of processes which provide decreasing of toxicity and accelerate excreting of the molecule of a drug or other foreign substance after its incoming into the organism complex of processes which provide decreasing of toxicity and accelerate excreting of the molecule of a drug or other foreign substance after its incoming into the organism (Chemical alteration of the drug in the body )

3. Metabolism of Drugs Aim: to convert non-polar lipid soluble compounds to polar lipid insoluble compounds to avoid reabsorption in renal tubules Aim: to convert non-polar lipid soluble compounds to polar lipid insoluble compounds to avoid reabsorption in renal tubules Most hydrophilic drugs are less biotransformed and excreted unchanged – streptomycin, neostigmine and pancuronium etc. Most hydrophilic drugs are less biotransformed and excreted unchanged – streptomycin, neostigmine and pancuronium etc. Biotransformation is required for protection of body from toxic metabolites Biotransformation is required for protection of body from toxic metabolites

6. Biotransformation of drugs into active (or more active) metabolites Initial drug Initial drug Allopurinol Allopurinol Amitriptilin Amitriptilin Acetylsalicylic acid Acetylsalicylic acid Butadion Butadion Diazepam Diazepam Digitoxin Digitoxin Codein Codein Cortizol Cortizol Methyldopa Methyldopa Prednison Prednison Novocainamid Novocainamid Propranolol Propranolol Active metabolite Aloxantin Aloxantin Nortriptilin Nortriptilin Salicylic acid Salicylic acid Oxyfenbutazon Oxyfenbutazon Dismethyldiazepam Dismethyldiazepam Digoxin Digoxin Morphine Morphine Hydrocortizon Hydrocortizon Methylnoradrenalin Methylnoradrenalin Prednisolon Prednisolon N-acetylnovocainamid N-acetylnovocainamid N-oxypropranolol N-oxypropranolol

7. ORGANS OF DRUGS METABOLISM liver liver kidneys kidneys muscle tissue muscle tissue intestinal wall intestinal wall lungs lungs skin skin blood blood

8. Reactions of biotransformation Nonsynthetic - І phase – metabolite may be active or inactive Nonsynthetic - І phase – metabolite may be active or inactive Synthetic - ІІ phase – metabolites are inactive (Morphine – M-6 glucoronide is exception) Synthetic - ІІ phase – metabolites are inactive (Morphine – M-6 glucoronide is exception) І phase (nonsynthetic reactions): (oxydation, reduction, hydrolysis) 1) microsomal reactions 1) microsomal reactions 2) nonmicrosomal reactions 2) nonmicrosomal reactions Reactions of І phase - transformation in molecule with formation of functional groups with active hydrogen atom Reactions of І phase - transformation in molecule with formation of functional groups with active hydrogen atom

10. The catalytic cycle of cytochrome P450 CYP-450 – hemoprotein, which is able to interact with substrate of oxydation, to activate oxygen and combine it with substrate. Specifically on CYР-450 reactions of hydroxydation are performed large amount of isoforms of this enzyme – possibility of its binding with different substrates and taking part in their metabolism large amount of isoforms of this enzyme – possibility of its binding with different substrates and taking part in their metabolism There are 24 isoforms of CYР-450 in microsomes of human liver Multiplicity of the enzyme has a group character: one isoform of CYР-450 interacts not only with one substrate but with a group of substances Multiplicity of the enzyme has a group character: one isoform of CYР-450 interacts not only with one substrate but with a group of substances

11. Phase I - Reduction This reaction is conversed of oxidation and involves CYP 450 enzymes working in the opposite direction. This reaction is conversed of oxidation and involves CYP 450 enzymes working in the opposite direction. Examples - Chloramphenicol, levodopa, halothane and warfarin Examples - Chloramphenicol, levodopa, halothane and warfarin Levodopa (DOPA) Dopamine DOPA- decarboxylase Levodopa (DOPA) Dopamine DOPA- decarboxylase

12. Phase I - Hydrolysis This is cleavage of drug molecule by taking up of a molecule of water. Similarly amides and polypeptides are hydrolyzed by amidase and peptidases. Hydrolysis occurs in liver, intestines, plasma and other tissues. This is cleavage of drug molecule by taking up of a molecule of water. Similarly amides and polypeptides are hydrolyzed by amidase and peptidases. Hydrolysis occurs in liver, intestines, plasma and other tissues. Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin

13. Phase II metabolism Conjugation of the drug or its phase I metabolite with an endogenous substrate - polar highly ionized organic acid to be excreted in urine or bile - high energy requirements Conjugation of the drug or its phase I metabolite with an endogenous substrate - polar highly ionized organic acid to be excreted in urine or bile - high energy requirements Glucoronide conjugation - most important synthetic reaction Glucoronide conjugation - most important synthetic reaction Compounds with hydroxyl or carboxylic acid group are easily conjugated with glucoronic acid - derived from glucose Compounds with hydroxyl or carboxylic acid group are easily conjugated with glucoronic acid - derived from glucose Examples: Chloramphenicol, aspirin, morphine, metroniazole, bilirubin, thyroxine Examples: Chloramphenicol, aspirin, morphine, metroniazole, bilirubin, thyroxine Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by bacteria, producing beta-glucoronidase - liberated drug is reabsorbed and undergoes the same fate - enterohepatic recirculation (e.g. chloramphenicol, phenolphthalein, oral contraceptives) and prolongs their action Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by bacteria, producing beta-glucoronidase - liberated drug is reabsorbed and undergoes the same fate - enterohepatic recirculation (e.g. chloramphenicol, phenolphthalein, oral contraceptives) and prolongs their action

16. Phase II metabolism – contd. Acetylation: Compounds having amino or hydrazine residues are conjugated with the help of acetyl CoA, e.g.sulfonamides, isoniazid Acetylation: Compounds having amino or hydrazine residues are conjugated with the help of acetyl CoA, e.g.sulfonamides, isoniazid Genetic polymorphism (slow and fast acetylators) Genetic polymorphism (slow and fast acetylators) Sulfate conjugation: The phenolic compounds and steroids are sulfated by sulfokinases, e.g. chloramphenicol, adrenal and sex steroids Sulfate conjugation: The phenolic compounds and steroids are sulfated by sulfokinases, e.g. chloramphenicol, adrenal and sex steroids

17. Phase II metabolism – contd. Methylation: The amines and phenols can be methylated. Methionine and cysteine act as methyl donors. Methylation: The amines and phenols can be methylated. Methionine and cysteine act as methyl donors. Examples: adrenaline, histamine, nicotinic acid. Examples: adrenaline, histamine, nicotinic acid. Ribonucleoside/nucleotide synthesis : activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy Ribonucleoside/nucleotide synthesis : activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy

18. Factors that influence on drug metabolism

22. Enzyme Inhibition One drug can inhibit metabolism of other – if utilizes same enzyme One drug can inhibit metabolism of other – if utilizes same enzyme However not common because different drugs are substrate of different CYPs However not common because different drugs are substrate of different CYPs A drug may inhibit one isoenzyme while being substrate of other isoenzyme – quinidine A drug may inhibit one isoenzyme while being substrate of other isoenzyme – quinidine Some enzyme inhibitors – Omeprazole, metronidazole, isoniazide, ciprofloxacin and sulfonamides Some enzyme inhibitors – Omeprazole, metronidazole, isoniazide, ciprofloxacin and sulfonamides

23. Microsomal Enzyme Induction CYP3A – antiepileptic agents - Phenobarbitone, Rifampicin and glucocorticoide CYP3A – antiepileptic agents - Phenobarbitone, Rifampicin and glucocorticoide CYP2E1 - isoniazid, acetone, chronic use of alcohol CYP2E1 - isoniazid, acetone, chronic use of alcohol Other inducers – cigarette smoking, charcoal broiled meat, industrial pollutants – CYP1A Other inducers – cigarette smoking, charcoal broiled meat, industrial pollutants – CYP1A Consequences of Induction: Consequences of Induction: Decreased intensity – Failure of OCPs Decreased intensity – Failure of OCPs Increased intensity – Paracetamol poisoning (NABQI) Increased intensity – Paracetamol poisoning (NABQI) Tolerance – Carbmazepine Tolerance – Carbmazepine Some endogenous substrates are metabolized faster – steroids, bilirubin Some endogenous substrates are metabolized faster – steroids, bilirubin

24. Influence of body weight on kinetics of drugs In exhausted patients – speeding up of elimination, that’s why it’ s appropriate to introduce the increased dose – 1+ 1 / 3 In exhausted patients – speeding up of elimination, that’s why it’ s appropriate to introduce the increased dose – 1+ 1 / 3 In patients with overweighting – retention of lipid-soluble drugs in the organism In patients with overweighting – retention of lipid-soluble drugs in the organism For these patients it’s suitable to correct the dose according to “ideal” body weight: For these patients it’s suitable to correct the dose according to “ideal” body weight: For men ІBW = 50 + [(Н - 150) : 2,5] For women ІBW = 45 + [(Н - 150) : 2,5] where Н – height in cm where Н – height in cm in case of normal body weight the dose is calculated counting on 1 kg of patient’s body weight in case of normal body weight the dose is calculated counting on 1 kg of patient’s body weight

25. Drug-Drug Interactions during Metabolism Many substrates are retained not only at the active site of the enzyme but remain nonspecifically bound to the lipid membrane of the endoplasmic reticulum. In this state, they may induce microsomal enzymes; depending on the residual drug levels at the active site, they also may competitively inhibit metabolism of a simultaneously administered drug.

26. Drug-Drug Interactions during Metabolism Enzyme-inducing drugs include various sedative- hypnotics, tranquilizers, anticonvulsants, and insecticides. Patients who routinely ingest barbiturates, other sedative-hypnotics, or tranquilizers may require considerably higher doses of warfarin (an oral anticoagulant) to maintain a prolonged prothrombin time. On the other hand, discontinuance of the sedative may result in reduced metabolism of the anticoagulant and bleeding—a toxic effect of the ensuing enhanced plasma levels of the anticoagulant. Similar interactions have been observed in individuals receiving various combination drug regimens such as antipsychotics or sedatives with contraceptive agents, sedatives with anticonvulsant drugs, and even alcohol with hypoglycemic drugs (tolbutamide).

27. Drug-Drug Interactions during Metabolism Simultaneous administration of two or more drugs may result in impaired elimination of the more slowly metabolized drug and prolongation or potentiation of its pharmacologic effects Both competitive substrate inhibition and irreversible substrate-mediated enzyme inactivation may augment plasma drug levels and lead to toxic effects from drugs with narrow therapeutic indices.

28. Drug-Drug Interactions during Metabolism Allopurinol both prolongs the duration and enhances the chemotherapeutic action of mercaptopurine by competitive inhibition of xanthine oxidase. Consequently, to avoid bone marrow toxicity, the dose of mercaptopurine is usually reduced in patients receiving allopurinol. Cimetidine, a drug used in the treatment of peptic ulcer, has been shown to potentiate the pharmacologic actions of anticoagulants and sedatives. The metabolism of the sedative chlordiazepoxide has been shown to be inhibited by 63% after a single dose of cimetidine; such effects are reversed within 48 hours after withdrawal of cimetidine.

29. PRESYSTEMIC ELIMINATION Presystemic elimination – extraction of the drug from blood circulatory system during it’s first going through the liver (first pass metabolism) – it leads to decreasing of bioavailability (and therefore, decreasing of biological activity) of drugs Presystemic elimination – extraction of the drug from blood circulatory system during it’s first going through the liver (first pass metabolism) – it leads to decreasing of bioavailability (and therefore, decreasing of biological activity) of drugs propranolol (anaprilin), labetolol, aminazin, acetylsalicylic acid, labetolol, hydralasin, isadrin, cortizone, lidokain, morphin, pentasocin, organic nitrates, reserpin propranolol (anaprilin), labetolol, aminazin, acetylsalicylic acid, labetolol, hydralasin, isadrin, cortizone, lidokain, morphin, pentasocin, organic nitrates, reserpin

30. Presystemic elimination

31. Elimination of the drugs drugs can be excreted in forms of metabolites or unchanged forms through different ways: kidneys, liver, lungs, intestines, sweat and mammary glands etc. drugs can be excreted in forms of metabolites or unchanged forms through different ways: kidneys, liver, lungs, intestines, sweat and mammary glands etc. Hydrophilic compounds can be easily excreted.

32. ELIMINATION OF DRUGS (cont’d) with bile – drugs and their metabolites with relative MM over 3000 enterohepatic (intestinal-liver) recirculation: cardiac glycosides, morphine, tetracyclines cardiac glycosides, morphine, tetracyclines are excreted with bile in unchanged condition (previously not metabolized): antibiotics of tetracyclines group, macrolides through lungs – gases and volatile substances: ether for narcosis, ftorotan, N 2 O, partly – camphor, iodides, ethanol through intestine: ftalasol, enteroseptol, magnesium sulfate through sweat glands: iodides, bromides, salicylates through bronchial, salivary glands: bromides, iodides with milk: get into organism of the baby – levomycetin, fenilin, reserpin, lithium remedies, meprotan, tetracyclines, sulfonamides etc.