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LOCUS OFLOCUS OF
Bound Drug Metabolites
* Schematic representation of the interrelationship of the absorption, distribution,
binding and excretion of a drug and its concentration at its locus of action.
DEFINITION -DEFINITION -
BIO derived from GREEK Word BIOS meaning lifeBIO derived from GREEK Word BIOS meaning life
Transformation meaning alteration /Transformation meaning alteration / changechange
AIMS AND OBJECTIVESAIMS AND OBJECTIVES
The mechanisms involved in theThe mechanisms involved in the
biotransformation / metabolism of drugs arebiotransformation / metabolism of drugs are
Biotransformation causes: -Biotransformation causes: -
1.1. Conversion ofConversion of PRODRUGPRODRUG toto ACTIVEACTIVE
2.2. Conversion ofConversion of DrugDrug toto Inactive FormInactive Form
3.3. Conversion of aConversion of a DrugDrug to ato a ToxicToxic MetaboliteMetabolite
AIMS AND OBJECTIVESAIMS AND OBJECTIVES
A clinician must be well informed about theseA clinician must be well informed about these
processes to treat the patients without exposingprocesses to treat the patients without exposing
them to the harmful effects of drugs.them to the harmful effects of drugs.
Drugs are eliminated by biotransformation andDrugs are eliminated by biotransformation and
excretion intoexcretion into URINEURINE oror BILEBILE..
Major site of drugs biotransformation isMajor site of drugs biotransformation is
ADVANTAGES OF ADMINISTRATION OF AADVANTAGES OF ADMINISTRATION OF A
► To make a drug tasteless and more stable e.g.To make a drug tasteless and more stable e.g.
Propoxyphene hydrocloride (bitter and unstable)Propoxyphene hydrocloride (bitter and unstable)
Propoxyphene Naphsylate (tasteless & stable).Propoxyphene Naphsylate (tasteless & stable).
► To make the drug more palatable e.g. ChloramphenicolTo make the drug more palatable e.g. Chloramphenicol
Palmitate is given instead of Chloramphenicol.Palmitate is given instead of Chloramphenicol.
► To improve the rate of absorption of a drug e.g.To improve the rate of absorption of a drug e.g.
Tal – Ampicillin, Piv – Ampicillin & Bac – Ampicillin areTal – Ampicillin, Piv – Ampicillin & Bac – Ampicillin are
given instead of Ampicillin.given instead of Ampicillin.
► To reduce the toxicity of a drug e.g. Tal – Ampicillin,To reduce the toxicity of a drug e.g. Tal – Ampicillin,
Piv – Ampicillin & Bac – Ampicillin are given insteadPiv – Ampicillin & Bac – Ampicillin are given instead
of Ampicillin.of Ampicillin.
► To increase the concentration of a drug at its site ofTo increase the concentration of a drug at its site of
action e.g. Levodopa in place of Dopamine.action e.g. Levodopa in place of Dopamine.
► To increase the duration of action of a drug e.g.To increase the duration of action of a drug e.g.
PhenothiazinePhenothiazine Fluphenazine (ester derivatives likeFluphenazine (ester derivatives like
Fluphenazine enanthate, Fluphenazine decanoate).Fluphenazine enanthate, Fluphenazine decanoate).
The kidney cannot efficiently eliminateThe kidney cannot efficiently eliminate
LipophilicLipophilic DrugsDrugs that readily cross cellthat readily cross cell
membrane and are reabsorbed in the distalmembrane and are reabsorbed in the distal
The lipid soluble agents must, therefore,The lipid soluble agents must, therefore,
undergo biotransformation in the liver.undergo biotransformation in the liver.
Drug biotransformation reactions are classified as:Drug biotransformation reactions are classified as:
PHASE 1 REACTIONSPHASE 1 REACTIONS
PAHSE 2 REACTIONSPAHSE 2 REACTIONS
Conjugation ReactionsConjugation Reactions
Conjugates are generally Inactive and areConjugates are generally Inactive and are
excreted rapidly in urine and fecesexcreted rapidly in urine and feces
DRUG BIOTRANSFORMATIONDRUG BIOTRANSFORMATION
► Pattern of ReactionsPattern of Reactions
Phase-I Reaction is often followed by Phase-II Reaction.Phase-I Reaction is often followed by Phase-II Reaction.
Drug or its metabolite produced from Phase-I Reaction is conjugated with an endogenousDrug or its metabolite produced from Phase-I Reaction is conjugated with an endogenous
substrate during Phase-II Reaction.substrate during Phase-II Reaction.
Phase-I Reaction (Drug or its Metabolite) Phase-II ReactionPhase-I Reaction (Drug or its Metabolite) Phase-II Reaction (Conjugation)(Conjugation)
► In some cases Phase-II reaction may precede phase-I reaction. e.g.In some cases Phase-II reaction may precede phase-I reaction. e.g.
Phase-II reaction (acetylation) take place first and is then followed byPhase-II reaction (acetylation) take place first and is then followed by
phase-I reaction (Hydrolysis) as under:-phase-I reaction (Hydrolysis) as under:-
Phase-II Phase-IPhase-II Phase-I
Acetylation HydrolysisAcetylation Hydrolysis
DRUG BIOTRANSFORMATIONDRUG BIOTRANSFORMATION
INHINH N-acetyl INHN-acetyl INH Isonicotinic acid + acetylhydazineIsonicotinic acid + acetylhydazine
EFFECTS OF PHASE-I REACTIONS ON THEEFFECTS OF PHASE-I REACTIONS ON THE
SOLUBILITY AND ACTIVITY OF A DRUGSOLUBILITY AND ACTIVITY OF A DRUG
a.a. Lipid solubility of drugs partially converted into water solubility.Lipid solubility of drugs partially converted into water solubility.
b.b. Sometimes water solubility may be decreasedSometimes water solubility may be decreased
(diazepam desmethyldiazepam)(diazepam desmethyldiazepam)
c.c. A drug may be inactivated, activity may be increased or activity may beA drug may be inactivated, activity may be increased or activity may be
totally modified producing a highly toxic/ reactive / carcinogenictotally modified producing a highly toxic/ reactive / carcinogenic
► Parathion is converted into highly toxic paraoxon.Parathion is converted into highly toxic paraoxon.
► Acetaminophen (Paracetamol) is converted intoAcetaminophen (Paracetamol) is converted into
highly toxic product (N-acetyl-p-highly toxic product (N-acetyl-p-
► Diazepam converted to Oxazepam witch is moreDiazepam converted to Oxazepam witch is more
d. On biotransformation, a drug may yield more than one active/ inactive
metabolites, some of them having longer half-life than that of the parent
drug. Diazepam NordazepamDiazepam Nordazepam
Effects of Phase – II Reactions on DrugsEffects of Phase – II Reactions on Drugs
aa. Generally. Generally Lipid solubility of drugs isLipid solubility of drugs is totally converted intototally converted into
water solubilitywater solubility..
b.b. Drugs areDrugs are generally inactivatedgenerally inactivated..
c.c. Sometimes drug is activated e.g.Sometimes drug is activated e.g.
Minoxidil is converted into active Minoxidil -o- sulphate.Minoxidil is converted into active Minoxidil -o- sulphate.
Morphine converted into active Morphine-6-glucuronide.Morphine converted into active Morphine-6-glucuronide.
dd. Conjugates may be secreted into the bile by an active transport. Conjugates may be secreted into the bile by an active transport
process;process; may be split up by the intestinal bacteriamay be split up by the intestinal bacteria causingcausing
release and reabsorption of active drug, thus establishingrelease and reabsorption of active drug, thus establishing
entero-hepatic circulation of the active drug prolonging itsentero-hepatic circulation of the active drug prolonging its
duration of actionduration of action
e.g. Doxycyline, oral contraceptive combined-pill.e.g. Doxycyline, oral contraceptive combined-pill.
GENETIC FACTORS.GENETIC FACTORS.
Atypical pseudocholinesterase:-Atypical pseudocholinesterase:- SuccinylcholineSuccinylcholine
(Suxamethonium) is hydrolysed by pseudocholinesterase.(Suxamethonium) is hydrolysed by pseudocholinesterase.
Genetically abnormal pseudocholinesterase Apnoea.Genetically abnormal pseudocholinesterase Apnoea.
Acetylation status:Acetylation status: Slow & Fast acetylators Inherited as anSlow & Fast acetylators Inherited as an
autosomal recessive trait Slow acetylator phenotype – about 50autosomal recessive trait Slow acetylator phenotype – about 50
% 0f blacks & white in the USA Much less common in Asians &% 0f blacks & white in the USA Much less common in Asians &
Genetically determined defects in the CYP dependent oxidativeGenetically determined defects in the CYP dependent oxidative
metabolism of:metabolism of:
Debrisoquin, Phenacetin, Phenformin (extensive metabolizersDebrisoquin, Phenacetin, Phenformin (extensive metabolizers
and poor metabolizers)and poor metabolizers)
Hydroxylation of anticonvulsant Mephenytoin:Hydroxylation of anticonvulsant Mephenytoin: PoorPoor
hydroxylators & Fast hydroxylatorshydroxylators & Fast hydroxylators
► PATHOLOGICAL STATES OF:PATHOLOGICAL STATES OF:
► LIVER:-LIVER:- acute & chronic liver diseases, CA of liver depressacute & chronic liver diseases, CA of liver depress
metabolism of chloramphnical & diazepam increasing their plasmametabolism of chloramphnical & diazepam increasing their plasma
► CVS:-CVS:- CCF decreases hepatic perfusion decreasing the clearance ofCCF decreases hepatic perfusion decreasing the clearance of
► LUNGS:-LUNGS:- In pulmonary diseases, metabolism of procainamide andIn pulmonary diseases, metabolism of procainamide and
aminopyirne is depressed.aminopyirne is depressed.
► ENDOCRINES:-ENDOCRINES:- Hypothyroidism decreases the metabolism ofHypothyroidism decreases the metabolism of
digoxin, methimazole, practolol increasing their plasma half-life,digoxin, methimazole, practolol increasing their plasma half-life,
reverse happens in hyperthyroridism.reverse happens in hyperthyroridism.
► NUTRITIONAL STATUS:NUTRITIONAL STATUS:
► SPECIESSPECIES (Phenylbutazone, Pethidine, Barbiturates)(Phenylbutazone, Pethidine, Barbiturates)
► SEXSEX (Hexobarbitone, BDZs, Oestrogens,(Hexobarbitone, BDZs, Oestrogens,
ENZYME INHIBITORSENZYME INHIBITORS
• Competitive inhibitorsCompetitive inhibitors quinidinequinidine
• Reversible non - Competitive inhibitorsReversible non - Competitive inhibitors –– KETOCONAZOLEKETOCONAZOLE
• Suicide inhibitors- GestodeneSuicide inhibitors- Gestodene
ALLOBARBITONEALLOBARBITONE Suicide inhibitorsSuicide inhibitors
Inhibitors of intestinal P-gycoprotein (P-gp)Inhibitors of intestinal P-gycoprotein (P-gp)
Certain components of grape fruit juiceCertain components of grape fruit juice
Drugs expelled by P-gp are digoxin, cyclosporineDrugs expelled by P-gp are digoxin, cyclosporine
Competitive substrate inhibitionCompetitive substrate inhibition
►Sulphonamides inhibit the metabolism ofSulphonamides inhibit the metabolism of
►Phenylbutazone & coumarins inhibit thePhenylbutazone & coumarins inhibit the
metabolism of tolbutamide.metabolism of tolbutamide.
BIOTRANSFORMATIONBIOTRANSFORMATION usually results inusually results in
the loss of Pharmacological activity, but therethe loss of Pharmacological activity, but there
are exceptions.are exceptions.
PRODRUGPRODRUG →→ ACTIVE DRUGACTIVE DRUG
DRUGDRUG →→ MORE ACTIVE COMPOUNDMORE ACTIVE COMPOUND
DRUGDRUG →→ TOXIC COMPOUNDTOXIC COMPOUND