BIOTRANSFORMATION (METABOLISM)

Chemical alteration of drug in the body
Nonpolar compounds (lipid soluble) are converted to polar or lipid insoluble compounds, so that they are not reabsorbed in the renal tubules and excreted
Most hydrophilic drugs are little biotransformed & are excreted unchanged e.g. streptomycin

Biotransformation also help to protect the body from foreign substances or toxins
Sites for drug metabolism are liver (most important), kidney, intestine, lungs & plasma
Biotransformation may lead to :
Inactivation: most of the drugs are rendered inactive or less active e.g. paracetamol
Active metabolite from active drug: e.g. Morphine is converted to morphine-6-glucuronide
Activation of inactive drug: few drugs are inactive & need conversion in the body to active metabolite. Such a drug is called as Prodrug
Advantages of prodrug: more stable, better bioavailability & less side effects
e.g. LevodBiotransformation reactions can be classified into
A. nonsynthetic / phase I/ Functionalization reactions: A functional group is generated: metabolite may be active or inactive
B. Synthetic / Conjugation / Phase II reactions: metabolite is mostly inactive
opa is a prodrug, converted in the body to dopamine, which is active form
Nonsynthetic or Phase I reaction:
Oxidation: addition of oxygen / negatively charged radical or removal of hydrogen / positively charged radical
Most important drug metabolizing reactions
These reactions are carried out by an enzyme K/A monooxygenases in the liver
These reactions require a cytochrome P 450 haemoprotein, NADPH, cytochrome P 450 reductase & molecular oxygen
Importance of cytochrome oxidases: Few cytochrome isoenzymes (CYP3A4, CYP2C19) are important because their synthesis can be induced or inhibited by inducers & inhibitors respectively
Inducers & inhibitors are different for different isoenzymes
Important inducers are rifampicin, barbiturates, anticonvulsant drugs, cigarette smoke, charbroiled meat, polycyclic hydrocarbons etc
Important inhibitors are verapamil, diltiazem, ritonavir, grape fruit juice
Due to these inducers / inhibitors drug interactions may occur
Inducers will reduce the active amount while inhibitors will increase the active amount of drug
The other nonsynReduction
Hydrolysis
Cyclization
Decyclization
thetic reactions are
Synthetic or Phase II reaction:

Glucuronide conjugation
Acetylation
Methylation
Sulfate conjugation
Glycine conjugation
Glutathione conjugation
Ribonucleotide synthesis
Few drugs are metabolised by enzymes of intermediary metabolism e.g.
Alcohol : Alcohol dehydrogenase
Allopurinol: xanthine oxidase
Succinylcholine : plasma cholineesterase
Adrenaline: Monoamine oxidase

Microsomal enzymes:
Located on smooth endoplasmic reticulum, primarily in liver
Also present in kidney, intestine & lungs
Examples are cytochrome P450 (CYP3A4), glucuronyl transferase etc.
They catalyze most of the oxidation, reduction, hydrolysis & glucuronide conjugation
These are inducible by various drugs, diet & other agencies

Nonmicrosomal enzymes:
Present in cytoplasm & mitochondria of hepatocyte as well as in plasma
Not inducible
May show genetic polymorphism e.g. Pseudocholine esterases
Both microsomal & nonmicrosomal are deficient in newborn
Amount & kind of drug metabolising enzymes are controlled genetically
This is onHoffman elimination: inactivation of drug in the body by spontaneous molecular arrangement without the need of enzymes e.g. Atracurium
Inhibition of drug metabolism:
e of the major causes of individual variation in drug response
Mirosomal enzyme induction:
Many drugs, insecticide & carcinogen interact with DNA & increase the synthesis of microsomal enzyme protein e.g. cytochrome P450 & glucuronyl traansferase
As a result metabolism of inducing drug itself as well as of other drugs is increased
Different inducers are relatively selective for certain cytochrome P 450 enzyme families e.g. Anticonvulsant, rifampin: CYP3A4
Isoniazid & chronic alcohol : CYP2E1
Polycyclic hydrocarbons, cigarette smoke, charcoalbroiled meat & industrial pollutant : CYP1A
Induction take 4-14 days to reach its peak& is maintained till the inducing agent is given
Thereafter the enzyme returns to their original level over 1-3 weeks
Results of microsomal enzyme induction:
Decrease in intensity or duration of action of drugs that are inactivated by metabolism e.g. failure of contraception with OCP
Increased intensity of action of drugs that are activated by metabolism e.g. acute paracetamol toxicity
Tolerance if the drug induces its own metabolism
Precipitation of AIP
Intermittent use of inducer may interfere with adjustment of dose of another drug prescribed on regular basis e.g. oral anticoagulant, oral hypoglycemics, antiepileptics, antihypertensives etc
Application of enzyme induction:
Liver disease
Congenital nonhemolytic jaundice, phenobarbitone is given
Cushings syndrome: phenytoin may be given
Chronic poisoning: