SPECIFIC LEARNING OBJECTIVES - AT THE END OF THE
SEMINAR THE LEARNER WILL BE ABLE TO
1. Define and Describe Biotransformation of drugs
and Factors affecting it
2. Describe first pass metabolism
3. Describe the drug metabolizing enzymes
2. Describe Enzyme induction and inhibition
3. Describe the process of elimination of drugs
• Pharmacokinetics deals with Absorption, Distribution, Metabolism an
Excretion of the drugs.
• Pharmacon - drug
• kinesis - movement
• It is a branch which deals with “what the body does to the drug”.
• It is also called ADME study.
BIOTRANSFORMATION OF DRUGS
• Enzyme catalysed biochemical transformation of drugs within the living
• Lipid soluble to lipid insoluble - Not reabsorbed in kidney.
Intestine (small & large)
4 CONSEQUENCES OF BIOTRANSFORMATION
1. Inactive metabolite from active drug:
Eg - Paracetamol, propranolol, phenobarbitone, morphine, etc
2. Active metabolite from inactive (prodrug) or a less active drug:
Eg - L-Dopa Dopamine (in basal ganglia)
3. Active metabolite from an equally active drug:
Eg - Digitoxin Digoxin
Morphine Morphine - 6 - glucuronide
4. Formation of toxic metabolite:
Paracetamol N-acetyl-p-benzoquinoneimine (NAPQI)
Attributes of drugs with high first pass metabolism:
(a) Oral dose >> sublingual or parenteral dose.
(b) Marked individual variation in the oral dose due to differences in the extent of first
(c) Oral bioavailability is apparently increased in patients with severe liver disease.
(d) Oral bioavailability of a drug is increased if another drug competing with it in first pass
metabolism is given concurrently, e.g. chlorpromazine and propranolol.
CYP 450 SYSTEM
• Superfamily of heme containing sozymes located primarily in the smooth endoplasmic
reticulum of liver and GI tract.
• Metabolism of
1. Endogenous compounds (steroids and lipids)
2. Exogenous compounds - drugs, carcinogens, and environmental pollutants
• Metabolize only lipid soluble drugs
• Phase 1 (oxi, red, hyd) and phase 2 (glucuronyl conj)
• Many drugs, insecticides and carcinogens interact with DNA and increase the synthesis of
microsomal enzyme protein, especially cytochrome P-450 and UGTs.
CLINICAL SIGNIFICANCE OF ENZYME INDUCTION:
1. Decreased intensity and/or duration of action of drugs. e.g. Unwanted pregnancy -
failure of contraception with oral contraceptives, Phenytoin - ↑ metabolism of Vit D -
2. Increases intensity of drug action - Acute paracetamol toxicity in alcoholics
3. Tolerance - due to autoinduction - increase dose after 2 weeks. Eg - Carbamazepine,
4. Faster metabolism of endogenous substrates.
5. Interference with chronic toxicity testing
USES OF ENZYME INDUCTION
1. Congenital nonhaemolytic jaundice: deficient glucuronidation of bilirubin -
phenobarbitone hastens clearance of jaundice.
2. Cushing’s syndrome: phenytoin - enhances degradation of adrenal steroids.
3. Chronic poisonings: by faster metabolism of the accumulated poisonous substance.
• Rapid process, usually reversible
• Irreversible - secobarbital (antoinhibition of its own metabolism) - overdose
• Enzymes involved - Hepatic Microsomal mixed function oxidase (MFO), MAO,
Xanthine oxidase, etc.
DRUG CLEARANCE THROUGH METABOLISM
• Drug enters the body - elimination begins (Elimination - Biotransformation + excretion)
• 3 major pathways:
Clearance (CL) estimates the volume of blood from which the drug is cleared per unit of
Total CL - reflects all mechanisms of drug elimination
CL = Rate of elimination / plasma conc.
CL = 0.693 × Vd / t1/2
RATE OF ELIMINATION (R) OF PARTICULAR ORGAN
R = Amount of drug entering the organ per unit time -- Amount of drug leaving the organ per
R = Q.CA – Q.CV
Q is Rate of blood flow to that organ
CA is Concentration of drug in arteries entering that organ
CV is Concentration of drug in veins leaving that organ
Thus, R = Q. (CA – CV)
Since, CL = Rate of elimination / plasma conc.
CL = Q. (CA – CV) = Q. = Q x Extraction ratio.
Extraction ratio = CL / Q
HEPATIC EXTRATION RATIO
• Fraction of the absorbed drug prevented by the liver from reaching systemic circulation.
• Both presystemic metabolism as well as direct excretion into bile determine ERLiver,
• Orally given drugs - active metabolites reach the blood
• Parenterally give drug - directly reaches the blood
• So if active metabolites cause more ADR than the parent drug, Oral is less safe than
EXCRETION OF DRUGS
1. Breast milk
• Passive diffusion - lipid solubility, pH of urine and pKa of the drug.
• Acidic drugs are more reabsorbed - urinary pH - acidic
• In poisonings,
1. Acidification of urine by Ammonium chloride / Ascorbic acid / Acetazolamide
2. Alkalinization of urine by Sodium bicarbonate / sodium citrate
BILIARY EXCRETION AND ENTEROHEPATIC CIRCULATION
Drugs > 500 Da weight are secreted in bile
Conjugation with glucuronic acid increases the molecular weight of the substrate by almost 200 Da,
so bile is an important route for eliminating glucuronide conjugates.
Drugs eliminated via bile into feces:
Biliary Clearance = Biliary excretion rate
Plasma drug conc.
• A drug can be recycled between the gut lumen,
hepatic portal vein, liver, bile and back to the gut
• This is described as enterohepatic circulation.
• Some of the reabsorbed drug may escape hepatic
extraction and proceed into the hepatic vein,
maintaining the drug concentrations in the general
• Orally ingested drugs - not absorbed throughout the gut
1. Magnesium sulfate
• Gases and volatile liquids - breath
• Excretion depends on partial pressure of the gaseous drug in the blood, not on lipid
• Essential oils - eucalyptus oil and garlic oil - via cough / mucous expectoration.
EXCRETION THROUGH BREAST MILK
• pH partition principle
• Basic drugs - trapped in relatively acidic pH
of breast milk.
• Basc drugs secreted via breast milk:
5. Cytotoxic drugs
7. Oral contraceptives
• Non electrolytes:
Ethanol, urea - independent of milk pH.
• Acidic drugs secreted
DRUGS TO BE AVOIDED IN LACTATING MOTHER
• Nalidixic acid
TOTAL BODY CLEARANCE
• The total body (systemic) clearance, CLtotal, is the sum of all clearances from the drug-
metabolizing and drug-eliminating organs.
Care should be exercised while administering:
• renally excreted drugs;
• drugs with a narrow therapeutic index—digoxin;
• drugs which produce active metabolites
benzodiazepines (diazepam + chlordiazepoxide),
antipsychotics (risperidone, thioridazine), and
opioids (morphine, pethidine, dextropropoxyphene); and
• drugs that may further reduce renal function—NSAIDs.
FACTORS AFFECTING DRUG METABOLISM
5. Genetic variation
6. Nutrition and diet
8. Thyroid imbalance
9. Temporal factors
11. Drug-Drug interactions - Enzyme induction / inhibition
FACTORS AFFECTING DRUG METABOLISM
Neonates and infants - low microsomal enzymes and glucuronyl transferase.
The activity of CYP450 enzymes in neonates is <<< adult human
Grey baby syndrome - chloramphenicol
Floppy baby syndrome - Diazepam
Elderly age - ↓ Hepatic blood flow - slow metabolism of propranolol and pethidine - toxicity
Males - ↑ BMR - efficient metabolism - salicylates, alcohol, propranolol and
FACTORS AFFECTING DRUG METABOLISM
Atropine metabolism - Rabbits > Man
Eskimos metabolize drugs faster than Asians.
Chinese - ↑ alcohol dehydrogenase, ↓ Aldehyde dehydrogenase - More aldehydes in blood
- more symptoms of headache, palpitation.
5. NUTRITION AND DIET:
Protein rich diet - ↑ Metabolism of drugs
Carb rich diet - ↓ Metabolism of drugs
Starvation - enzyme inhibition.
KINETICS OF METABOLISM
• Plasma Half life (t1/2)
• Biological half life
• Biological effect half life
• Terminal half life
• Steady state concentration
• Plasma half life and Vd is very important to consider dosing schedule for any drug.
• 3 types of kinetics
Mixed order kinetics
• Significance of Plasma t½:
To know the,
The duration of action of the drug
The frequency of administration
The time needed for attainment of steady state concentration (SSC)—longer the t½,
longer is the time needed to attain SSC.
To calculate the loading and maintenance doses of the drug
STEADY STATE CONCENTRATION
• Repeated administration of drug at short intervals before complete elimination - Drug
accumulation in the body - rate of elimination equals rate of administration.
• It takes 4 - 5 half-lives for the plasma concentration to reach the plateau level.
FIRST ORDER KINETICS
• Drugs obey Michaelis–Menten kinetics, where Km is Michaelis constant (the substrate
concentration at half maximal velocity).
• In most clinical situations, Km >> [C]
• Rate of drug metabolism and elimination - directly proportional - concentration of free
• A constant fraction of drug is metabolized per unit of time (with each half-life, the
concentration decreases by 50%).
• Linear kinetics
ZERO ORDER KINETICS
• Here [C] >> Km
• Fixed amount of the drug is eliminated per unit time
• The rate of elimination is constant and does not depend on the drug concentration
• Non-linear kinetics
• Repeated drug administration over short intervals - lead to toxicity.
• The only way to speed the elimination process is to go for dialysis
• The enzyme is saturated by a high free drug concentration, and the rate of metabolism remains
constant over time.
MIXED ORDER KINETICS OR
MICHAELIS MENTON KINETICS OR
• Low dose - first order kinetics
• High doses - Zero order kinetics
• Eg - Aspirin, warfarin, digoxin, tolbutamide etc.
• Most of the drugs like phenytoin, undergo both first
and zero order kinetics at normal doses due to
saturation of enzymatic process
1. Goodman and Gilman - The pharmacological basis of therapeutics - 14th edition
2. Lippincott’s Pharmacology - First South Asian edition
3. K.D.Tripathi - Medical Pharmacology - 8th edition
4. Padmaja Udaykumar - Medical Pharmacology - 7th edition
5. HL & KL Sharma - Principles of Pharmacology - 3rd edition
6. Review of Pharmacology - Gobind Rai Gag - 14th edition
7. Brenner and Steven’s Pharmacology - 6th edition
Notas do Editor
Metabolism of a drug can begin even before a drug is absorbed: Gut bacteria represent the first metabolic interface between orally administered drugs and the body.
Interindividual differences in composition of the gut flora could influence drug action and contribute to differences in drug response
Xenobiotic-metabolizing enzymes can produce electrophilic metabolites that react with nucleophilic cellular macromolecules such as DNA, RNA, and protein. This can cause cell death and organ toxicity – Carcinogenesis.
This potential for carcinogenic activity makes testing the safety of drug candidates vitally important. Testing for cancer-causing potential is particularly critical for drugs that will be used for the treatment of chronic diseases.
Other organs that contain significant xenobiotic metabolizing enzymes include tissues of the nasal mucosa and lung, which play important roles in the metabolism of drugs that are administered through aerosol sprays. These tissues are also the first line of contact with hazardous substances that are airborne.
Prodrugs bioactivated by CYPs are the antitumor drug cyclophosphamide, which is bioactivated to a cell-killing electrophilic derivative.
Anti-thrombotic agent clopidogrel, which is activated to 2-oxo-clopidogrel and further metabolized to an irreversible inhibitor of platelet ADP P2Y12 receptors.
The liver is the major “metabolic clearinghouse” for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, and proteins) and xenobiotics.
The phase 1 enzymes lead to the introduction of functional groups, such as –OH, –COOH, –SH, –O–, or NH2.
The phase 1 oxidation reactions are carried out by CYPs, FMOs, and epoxide hydrolases (EHs). The CYPs and FMOs are composed of superfamilies and subfamilies encoded by multiple genes. The phase 2 enzymes include several superfamilies of conjugating enzymes. Among the more important are the glutathione-S-transferase (GSTs), UGTs, sulfotransferases (SULTs), N-acetyltransferases (NATs), and methyltransferases (MTs).
The conjugation reactions of the phase 2 enzymes usually require the substrate to have oxygen (hydroxyl or epoxide groups), nitrogen, or sulfur atoms that serve as acceptor sites for a hydrophilic moiety, such as glutathione, glucuronic acid, sulfate, or an acetyl group, that can be covalently conjugated to an acceptor site on the substrate.
Induction involves microsomal enzymes in liver as well as other organs and increases the rate of metabolism by 2–4 fold. Induction takes 4–14 days to reach its peak and is maintained till the inducing agent is being given. Thereafter the enzymes return to their original value over 1–3 weeks.
Plasma half-life (t½) is the time taken for the plasma concentration of a drug to be reduced to half its value
Biological half-life is the time required for total amount of drug in the body to be reduced to half.
Biological effect half-life is the time required for the biological effect of the drug to reduce to half.
Terminal half-life: On long-term use, certain drugs may remain in secondary compartments and they get gradually released into the circulation as the plasma concentration of drugs fall.