Download biotransformation

Biotransformation
Prepared by
Prof .Abdulkader.H.El Daibani
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Biotransformation
Biotransformation (metabolism) of
drugs:
 As most drugs are lipid soluble and
be reabsorbed, biotransformation is
essential for termination of action and
elimination of drugs.
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Biotransformation
Drug metabolism lead to:
1) Increase polarity of drugs by converting lipid soluble
drugs into water soluble drugs and therefore enhance
excretion.
2) Inactivation of drugs:
a) most drugs form inactive metabolites.
b) With some drugs both the parent drug and the
metabolite are active.
e.g.
Diazepam
Herion
→
→
oxazepam
Morphine
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Biotransformation
c) Other drugs, the parent drug is inactive
(prodrug) and the metabolite is active and
formed by hydrolysis of an ester or amide
bond e.g.
L-dopa
→
→
Talampicillin
→
enalapril
enalaprilate
dopamine
ampicillin
Cyclophosphamide → 4-ketocyclophosphamide
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Biotransformation
 Loss of activity or formation of active
metabolites occurs mainly in phase I
reaction where a functional group is
introduced or exposed. if not rapidly
excreted in urine, the metabolites of
phase I undergo conjugation in phase
II reactions to form highly polar
conjugates which are generally
inactive and rapidly excreted renally.
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Biotransformation
Sites of drug metabolism:
 The liver is the major organ of drug
metabolism, although other sites (lungs,
kidneys, plasma, small intestine. Placenta,
skin and brain) may contribute.
 Cytochrome P450 monooxygenase or mixed
function oxidase (M.F.O) system is the
major catalyst of drug biotransformation
reaction and located in smooth endoplasmic
reticulum (SER) of liver and other tissues.
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Biotransformation
 Enzymes presented in S.E.R are called Microsomal
enzyme.
 Non-microsomal enzymes are located in mitochondria
cytosole phase I enzyme are located in S.E.R. while
phase II enzyme are located in the cytosol.
 Most drugs are metabolized by phase I (oxidation)
followed by phase II (conjugation) with glucouronic
acid in some cell.
e.g.
PI
PII
paracetamol
( p)
→
Oxi
P-OH
→
P-OH-Gu
Conj.
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Biotransformation
 In human 12 cytochrome P450 gene
families have been identified.
The cyto.P450 1, P4502, P4503,(CYP1,
CYP2,CYP3).
Encode the enzyme involved in the majority of
drug transformation.
CYP3A4,CYP2D6 are involved in the metabolism
of all drugs. as a result of low substrate
specificity among cyt.P450 proteins, two or
more enzymes may catalyze a given
metabolic reaction.
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Biotransformation
Biochemical pathways of drug biotransformation
1)phase I (Non synthetic) reactions :
 loss of activity or formation of active metabolites occur in
phase I ,enzyme of phase I located in S.E.R.
a) Oxidation:
Most important phase I reactions and involve (M.O.F) system.
 Aliphatic oxidation: tolbutamide,Ibuprofen.
 Aromatic oxidation: propranolol, phenytoin
 S oxidation: cimetidine, chloropromazine(CPZ)
 N-Oxidation: paracetamol,dapsone.
 N-dealkylation: morphine,imipramine.
 O-dealkylation: codeine,indomethacin.
 Oxidation deamination : diazepam,amphetamine.
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Biotransformation
Cytochrome P450 independent oxidation
 Amine oxidases (M.AO) sympathomimetic
(adrenaline, Noradrenaline)
 Dehydrogenase-ethanol.
Oxidative stress:
is a harmful consequence of drug oxidation
leading to toxicity or carcinogenicity due to
formation of highly reactive
intermediates(FR) (free radicals) capable of
damaging specific cellular components, also
some diseases e.g. parkinsonism may be
due to oxidative stress.
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Biotransformation
b)Reduction:
 Microsomal and non microsomal.
 Nitroreduction Chloramphenicol, clorazepate .
c) hydrolysis:
 ester-succinylcholine, aspirin, procaine by non
specific estrase in liver and other tissue.
 Amide –Lidocaine, Indomethacin by specific estrase
in liver.
 Peptide-insulin, vasopressin by protease and
peptidases in plasma, erythrocyte and other tissue.
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Biotransformation




II) phase II (conjugation) reactions:
Also called synthetic reaction because drug or metabolite
binds with polar endogenous substance to form water
soluble conjugate which is readily eliminated by kidney or in
bile>300 in M.W.
The drug must possess a chemically active group (mainlyOH introduced-phase I) to which the conjugation substance
is attached.
The most imp. conjugation reactions are:
a) Glucuronidation.
b) Sulphation.
c) Acetylation.
d) Methylation.
e) Conjugation with glutathione.
f) Conjugation with amino acids.
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Biotransformation
a) Glucuronidation
 Most common phase II reaction. Catalyzed by
glucuronyl transferase in S.E.R. in liver, kidney and
other tissues in presence of uridie diphosphate
glucuronate (DP-G) as glucuronate donor to form
glucaronides which are:
1) Generally inactive
 But morphine glucuronide is more active than
morphine as analgesic.
2) rapidly excreted by kidney and bile by an anion
transport mechanism.
3) May be hydrolyzed by β-glucuronidase of intestinal
bacterial flora to produce the parent drug which is
reabsorbed from S.I (E.H circulation).
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Biotransformation
 Examples:
 Bilirubin, morphine, stilbesterol and chlormphenicol is
C.I. in neonates because it may cause grey baby
syndrome due to deficiency of glucuronyl transferase
in neonates.
 Most biotransformation reaction are oxidation followed
by glucuronidation.
oxi.
 Paracetamol
Glu.
→
para-OH → para-O-Glu
phaseI
phase II
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Biotransformation
b) Sulphation

In presence of 3-phosphadenosin, 5-phosphosulphate, steroids, heparin
and α methyl dopa.
c) Acetylation catalyzed by N-acetyl transferase in presence of acetyl CoA as an
acetyl group donnar limited to drug with primary-NH2.

e.g. Isonaizid , sulphonamides, hydralazine.

People who are genetically deficient in N-acetyl transferase are called slow
acetylators and they may exhibit adverse effects from these drugs e.

INH
→
Peripheral neuropathy
slow acetylator

Hyralazine and procainamide
→
slow acetylator
S.L.E
( Systemic lupus erythrmatosus)
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Biotransformation
d) Methylation
 Addition of methyl group via methionine in presence
of COMT e.g. metabolism of adrenaline and
histamine.
e) Conjugation with glutathione
 Binds with unstable potentially toxic intermediate
metabolites e.g. epoxide, paracetamol metabolite to
form non harmful compounds.
f) Conjugation with amino acids (Glycine and glutamine)
 e.g. conjugation of aromatic carboxylic acids such as
salicylic acid, benzoic acid and nicotinic acid with
glycine .
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Biotransformation
Factors affecting biotransformation
1) Enzyme induction and enzyme inhibition.
2) Genetic polymorphism (oxidation,conjugation)genetic
differences in the metabolism of drugs e.g. Isoniazid
(INH) slow acetylation and fast acetylation.
3) Environmental pollutants –smoking, insecticides e.g
D.D.T. (enzyme induction).
4) Pathological factors: liver disease, heart failure and
shock (↓ hepatic blood flow).
5) Age: drug metabolism is reduced in extremes of age.
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Biotransformation
1)enzyme induction and enzyme
inhibition:some drugs stimulate
(induction ) or inhibit microsomal
enzymes in liver.
a) Enzyme induction: causes increased
activity of microsomal enzyme.
 Involves de novo (synthesis of new
protein).
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Biotransformation
Characteristics of enzyme induction
1) reversible process.
2) Takes one week to appear and 2-3 weeks to disappear after
stopping drug.
3) ↑ weight and size of liver due to hypertrophy of hepatocytes.
 Some drugs increase metabolism of other drugs and their
own metabolism (Autoinduction) e.g. Carbamazepine.
 Inducing agents are specific for a given P450 family e.g.
polycyclic aromatic hydrocarbons, cigeratte smoking and
barbequed meat →↑CYP1A family.
 Glucocorticoids and anticonvulsants →↑CYP3A4 family .
 Acetone and chronic alcohol →↑ CYP2E1 family.
 Many inducers of cyt. P450 induce enzyme involved in
phase II reaction e.g. Glucuronyl transferase and
glutathione transferase .
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Biotransformation
Characteristics of inducing agent
1) lipid soluble.
2) Is a substrate for the enzyme it induces.
3) Has long t 1/2.
 1) Clinically importance of enzyme
inductions may occur e.g. failure of oral
contraceptive or loss of anticoagulant,
effect of warfarin following Rifampin.
 2) Pharmacokinetic tolerance due to
antiinduction with antiepileptic drug e.g.
carbamazepine and others.
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Biotransformation
 3) useful in therapy- phenobarbitone
induces bilirubin conjugation so used
in treatment of Hyperbilirubinemia.
 4) Disease may result ( Itarogenic
Effect) antiepilptics ↑ metabolism and
elimination of vit.D → leads to vit. D
deficiency→ osteomalasia in adults
or rickits in children.
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Biotransformation
B) Enzyme Inhibition
 Reduction in enzyme activity after exposure to some
drugs e.g. cimetidine and ketoconazol inhibit
oxidation of drugs by forming tight complex with
heam-iron of cyp P450.
 Erythromycin inhibit CYP3A and its metabolites to form
a complex with heam of iron of CYP 450.
 Other enzyme inhibitors include INH, sodium
valproate, metronidazole and ciprofloxacin.
 Enzyme inhibition tend to be more selective than
enzyme induction.
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Biotransformation
Enzyme inhibitor
Cimetidine
Chloramphenicol
Erythromycin
↓metabolism of
clinical effect
warfarin
bleeding
tolbutamide
hypoglycemia
terfenadineor astrmizole
arrthmias
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