Drug Biotransformation

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Drug Biotransformation

• Elimination of the drugs

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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
• (Chemical alteration of the drug in the body )

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Metabolism of Drugs

• 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.
• Biotransformation is required for protection of
  body from toxic metabolites

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Results of Biotransformation

• Active drug and its metabolite to inactive
  metabolites most drugs (ibuprofen, paracetamol,
  chlormphenicol etc.)
• Active drug to active product (phenacetin
  acetminophen or paracetamol, morphine to
  morphine-6-glucoronide, digitoxin to digoxin
  etc.)
• Inactive drug to active/enhanced activity
  (prodrug) levodopa - carbidopa, prednisone
  prednisolone and enalapril enalaprilat)
• No toxic or less toxic drug to toxic metabolites
  (Isonizide to Acetyl isoniazide)

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Biotransformation of drugs into active (or more
active) metabolites

• Active metabolite
• Aloxantin
• Nortriptilin
• Salicylic acid
• Oxyfenbutazon
• Dismethyldiazepam
• Digoxin
• Morphine
• Hydrocortizon
• Methylnoradrenalin
• Prednisolon
• N-acetylnovocainamid
• N-oxypropranolol

• Initial drug
• Allopurinol
• Amitriptilin
• Acetylsalicylic acid
• Butadion
• Diazepam
• Digitoxin
• Codein
• Cortizol
• Methyldopa
• Prednison
• Novocainamid
• Propranolol

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ORGANS OF DRUGS METABOLISM

• liver
• kidneys
• muscle tissue
• intestinal wall
• lungs
• skin
• blood

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Reactions of biotransformation

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

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Phase I - Oxidation

• Most important drug metabolizing reaction
  addition of oxygen or (ve) charged radical or
  removal of hydrogen or (ve) charged radical
• Various oxidation reactions are oxygenation or
  hydroxylation of C-, N- or S-atoms N or
  0-dealkylation
• Examples Barbiturates, phenothiazines,
  paracetamol and steroids

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Phase I - Oxidation

• Involve cytochrome P-450 monooxygenases (CYP),
  NADPH and Oxygen
• More than 100 cytochrome P-450 isoenzymes are
  identified and grouped into more than 20 families
  1, 2 and 3
• Sub-families are identified as A, B, and C etc.
• In human - only 3 isoenzyme families important
  CYP1, CYP2 and CYP3
• CYP 3A4/5 carry out biotransformation of largest
  number (3050) of drugs. In addition to liver,
  this isoforms are expressed in intestine
  (responsible for first pass metabolism at this
  site) and kidney too
• Inhibition of CYP 3A4 by erythromycin,
  clarithromycin, ketoconzole, itraconazole,
  verapamil, diltiazem and a constituent of grape
  fruit juice is responsible for unwanted
  interaction with terfenadine and astemizole
• Rifampicin, phenytoin, carbmazepine,
  phenobarbital are inducers of the CYP 3A4

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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
  CY?-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
• There are 24 isoforms of CY?-450 in microsomes
  of human liver
• Multiplicity of the enzyme has a group
  character one isoform of CY?-450 interacts not
  only with one substrate but with a group of
  substances

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Microsomal enzyme system

• Oxydoreductases, esterases, enzymes of
  proteins, lipids, glycerophosphatides, lipo- and
  glycoproteids, bile acids, cholesterol,
  prostaglandins biosynthesis, enzyme systems of
  biosynthesis of couple compounds, ethers of
  glucuronic and sulfur acids

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Oxydoreductases of microsomes (oxygenases of
microsomes, microsomal hydroxydating system,
NADPH-hydroxylase system, monooxygenases of
mixed functions)

• these are enzymes which activate molecular
  oxygen and catalize including of one
  (monooxygenase) or two (dioxygenases) atoms of
  oxygen into molecule of substrate (R) Reaction is
  presented as follows
• R O2 D? ROH H2O D
• One atom of ?2 is included into molecule of
  the substrate, other is reduced to ?2?, therefore
  enzyme performs oxygenase and oxydase functions
  simultaneously. Thats why monooxygenases ate
  also called oxydases of mixed function. Along
  with this hydroxyl group (-??) forms in molecule
  of substrate, thats why monooxygenase is also
  calles hydroxylating system, and reaction of
  oxydation oxydating hydroxylation

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Nonmicrosomal Enzyme Oxidation

• Some Drugs are oxidized by non-microsomal enzymes
  (mitochondrial and cytoplsmic) Alcohol,
  Adrenaline, Mercaptopurine
• Alcohol Dehydrogenase
• Adrenaline MAO
• Mercaptopurine Xanthine oxidase

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Phase I - Reduction

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

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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.
• Examples - Choline esters, procaine, lidocaine,
  pethidine, oxytocin

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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
• Glucoronide conjugation - most important
  synthetic reaction
• Compounds with hydroxyl or carboxylic acid group
  are easily conjugated with glucoronic acid -
  derived from glucose
• 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

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Phase II metabolism contd.

• 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)
• Sulfate conjugation The phenolic compounds and
  steroids are sulfated by sulfokinases, e.g.
  chloramphenicol, adrenal and sex steroids

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Phase II metabolism contd.

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

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Main ways of biotransformation of drugs

• I phase
• Oxydation diazepam, pentazocin, sydnocarb,
  phenotiazin, phenobarbital, aspirin, butadion,
  lidokain, morphin, codein, ethanol, rifampicin
• Reduction hestagens, metronidazol, nitrazepam,
  levomycetin, chlozepid
• Hydrolysis levomycetin, novocain, cocain,
  glycosides, ditilin, novocainamid, xycain,
  fentanyl
• II phase
• Conjugation with sulfate morphin, paracetamol,
  isadrin
• Conjugation with glucuronic acid teturam,
  sulfonamides, levomycetin, morphin
• Conjugation with remains of ? -
  aminoacids nicotinic acid, paracetamol
• Acetylation sulfonamides, isoniasid,
  novocainamid
• Methylation morphin, unitiol, ethionamid,
  noradrenalin

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Metabolism in the intestinal wall

• Synthetic and nonsynthetic reactions take place
• Isadrin conjugation with sulfate
• Hydrlalasin - acetylation
• Penicillin, aminazin metabolism with
  nonspecific enzymes
• Methotrexat, levodopa metabolism with
  intestinal bacteria

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Factors affecting Biotransformation

• Concurrent use of drugs Induction and inhibition
  
• Genetic polymorphism
• Pollutant exposure from environment or industry
• Pathological status
• Age

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Factors that influence on drug metabolism
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Enzyme Inhibition

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

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Microsomal Enzyme Induction

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

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Influence of body weight on kinetics of drugs

• In exhausted patients speeding up of
  elimination, thats why it s appropriate to
  introduce the increased dose 11/3
• In patients with overweighting retention of
  lipid-soluble drugs in the organism
• For these patients its suitable to correct the
  dose according to ideal body weight
• For men ?BW 50 (? - 150)
  2,5
• For women ?BW 45 (? - 150) 2,5
• where ? height in cm
• in case of normal body weight the dose is
  calculated counting on 1 kg of patients body
  weight

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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.

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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
  bleedinga 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).

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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.

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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.

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PRESYSTEMIC ELIMINATION

• Presystemic elimination extraction of the
  drug from blood circulatory system during its
  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

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Presystemic elimination
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Clinical Relevance of Drug Metabolism

• The dose and the frequency of administration
  required to achieve effective therapeutic blood
  and
• tissue levels vary in different patients because
  of individual differences in drug distribution
  and
• rates of drug metabolism and elimination. These
  differences are determined by genetic factors and
• nongenetic variables such as age, sex, liver
  size, liver function, circadian rhythm, body
  temperature,
• and nutritional and environmental factors such as
  concomitant exposure to inducers or inhibitors of
• drug metabolism.

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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.
• Hydrophilic compounds can be easily excreted.

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Elimination through kidneys

• filtration, canalicular secretion and
• canalicular reabsorption
• filtration (relative molecular weight of drugs is
  less than 90,
• if 90-300 with urine and bile) ampicillin,
  gentamicin, urosulfan, novokainamid, digoxin
• Disorders of filtration shock, collapse (due to
  decreasing of blood circulation and hydrostatic
  pressure of blood plasma in glomerular
  capillaries)
• furosemide (closely connected with plamsa
  proteins) is not filtrated in glomerular
  capilaries
• canalicular secretion active process (with the
  aid of enzyme system and using energy)
  penicillins, furosemide, salicilates, chinin
• Disorders of canalicular secretion in case of
  disorders of energetic metabolism in kidneys
  hypoxia, infections, intoxications

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Glomerular Filtration

• Normal GFR 120 ml/min
• Glomerular capillaries have pores larger than
  usual
• The kidney is responsible for excreting of all
  water soluble substances
• All nonprotein bound drugs (lipid soluble or
  insoluble) presented to the glomerulus are
  filtered
• Glomerular filtration of drugs depends on their
  plasma protein binding and renal blood flow -
  Protein bound drugs are not filtered !
• Renal failure and aged persons

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Tubular Re-absorption

• Back diffusion of Drugs (99) lipid soluble
  drugs
• Depends on pH of urine, ionization etc.
• Lipid insoluble ionized drugs excreted as it is
  aminoglycoside (amikacin, gentamicin, tobramycin)
  
• Changes in urinary pH can change the excretion
  pattern of drugs
• Weak bases ionize more and are less reabsorbed in
  acidic urine.
• Weak acids ionized more and are less reabsorbed
  in alkaline urine
• Utilized clinically in salicylate and barbiturate
  poisoning alkanized urine (Drugs with pKa 5
  8)
• Acidified urine atropine and morphine etc.

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Tubular reabsorbtion (reversed absorbtion)

• lipid-soluble drugs are reabsorbed passively
• ionized drugs, which are weak acids or alkali
  are reabsorbed actively
• regulation of level of reabsorbtion
• - to speed up elimination of drugs weak
  alkalis (antihistamine drugs, chinin,
  theophyllin) urine is made acidic (with
  ascorbinic acid, ammonium chloride)
• - to speed up elimination of drugs weak acids
  (NSAID, including ASA, barbiturates,
  sulfonamides) urine is made alkaline
  (introduction of sodium hydrocarbonate)

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Tubular Secretion

• Energy dependent active transport reduces the
  free concentration of drugs further, more drug
  dissociation from plasma binding again more
  secretion (protein binding is facilitatory for
  excretion for some drugs)

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ELIMINATION OF DRUGS (contd)

• with bile drugs and their metabolites with
  relative MM over 3000
• enterohepatic (intestinal-liver) recirculation
• 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, N2O, 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.