Dr. Arun.S
First year Post Graduate
Department of Pharmacology
Government Medical College
Ananthapuramu

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

DEFINITION
• 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
organism.
• Lipid soluble to lipid insoluble - Not reabsorbed in kidney.
• Sites:
Liver (m.c)
Kidney
Lungs
Intestine (small & large)
Adrenal cortex
Placenta
Skin

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)
Prednisone Prednisolone
Enalapril Enalaprilat
Dipivefrine Epinephrine

3. Active metabolite from an equally active drug:
Eg - Digitoxin Digoxin
Morphine Morphine - 6 - glucuronide
Allopurinol Alloxanthine
4. Formation of toxic metabolite:
Eg:
Paracetamol N-acetyl-p-benzoquinoneimine (NAPQI)
Cyclophosphamide Acrolein

TO SUMMARISE:

FIRST PASS METABOLISM
• Pre-systemic metabolism
• First pass effect

HEPATIC FIRST PASS METABOLISM

HEPATIC FIRST PASS METABOLISM OF SOME DRUGS

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
pass metabolism.
(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.

CHEMICAL PATHWAYS OF DRUG BIOTRANSFORMATION

PHASE - 1 REACTIONS
• Degradative reactions
• Metabolite formed - active / inactive
• Mostly CYP mediated.
• Introduction of a new group - smaller non-polar / polar

PHASE - 2 REACTIONS
• Conjugation reactions
• Catalysed by Microsomal, mitochondrial or cytoplasmic enzymes
• Metabolite - polar, water soluble - inactive

INDUCERS
INHIBITORS

Summarise the reactions

PHASE - 3
• ATP-binding cassette (ABC) and solute linked carrier (SLC) transporters.
• ABC transporters - efflux (Primary active transport)
• SLC - Uptake and efflux (Secondary active transport - symport and antiport)
• Uptake transporters:
1. Na+-taurocholate cotransporting polypeptide (NTCP)
2. OCT 1
3. OAT 2
4. organic anion-transporting polypeptides
• Efflux transporters:
1. P-gp efflux system
2. bile salt export pump (BSEP)
3. multidrug resistance-associated protein (MRP) 2

INHIBITOR INDUCER

DRUG METABOLIZING ENZYMES
• MICROSOMAL ENZYMES
• NON-MICROSOMAL ENZYMES

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)

CYP 450 SYSTEM
• NOMENCLATURE:

NON-MICROSOMAL ENZYMES
• Located in cytoplasm, mitochondria - liver cells (m.c) and plasma
• Eg - MAO, Esterases, amidases, transferases
• Phase 2 reactions (except glucuronide conj)
• Few Phase 1 reactions (oxi, red, hyd)
• Non-inducible
• Can be inhibited

NON-ENZYMATIC BIOTRANSFORMATION (HOFFMANS
ELIMINATION)
• Inactivation of the drug in body fluids spontaneously by molecular rearrangement.
• Eg - Atracurium, Cisatracurium, Gantacurium

ENZYME INDUCTION
• 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 -
Osteomalacia
2. Increases intensity of drug action - Acute paracetamol toxicity in alcoholics
3. Tolerance - due to autoinduction - increase dose after 2 weeks. Eg - Carbamazepine,
rifampin, nevirapine
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.

ENZYME INHIBITION
• Rapid process, usually reversible
• Irreversible - secobarbital (antoinhibition of its own metabolism) - overdose
• Enzymes involved - Hepatic Microsomal mixed function oxidase (MFO), MAO,
Xanthine oxidase, etc.

CLINICAL RELEVANCE OF ENZYME INHIBITION
POTENTIALLY ADVERSE CONSEQUENCES:
• Nausea / vomitting - Theophylline + Erythromycin
• ↑ Bleeding - cimetidine + warfarin
• Severe RS depression - Morphine + MAO inhibitors
• Ataxia & drowsiness - Phenytoin + Warfarin / chloramphenicol
• Cardiac arrhythmias - Terfenadine + ketoconazole / chloramphenicol

THERAPEUTICALLY BENEFICIAL CONSEQUENCES:
• ↑ L-dopa in brain when given with Carbidopa
• Alcohol deaddiction with disulfiram
• d-tubocurarine induced skeletal muscle paralysis - reversed by neostigmine

DRUG CLEARANCE THROUGH METABOLISM
• Drug enters the body - elimination begins (Elimination - Biotransformation + excretion)
• 3 major pathways:
hepatic metabolism,
biliary elimination,
urinary excretion.
Clearance (CL) estimates the volume of blood from which the drug is cleared per unit of
time.
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
unit time
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.
Q. CA
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
parenteral route.

EXCRETION OF DRUGS
Major routes
1. Renal
2. Biliary
3. Faecal
4. Alveolar
Minor routes
1. Breast milk
2. Skin
3. Hair
4. Sweat
5. Saliva

RENAL EXCRETION

RENAL EXCRETION
GLOMERULAR FILTRATION
Non selective and unidirectional process
Factors affecting it:
• Molecular size
• Plasma protein binding
• Renal blood flow

RENAL EXCRETION
ACTIVE TUBULAR SECRETION
80% drugs eliminated
PPB - doesnt interfere

RENAL EXCRETION
TUBULAR REABSORPTION
• Passive diffusion - lipid solubility, pH of urine and pKa of the drug.
• Acidic drugs are more reabsorbed - urinary pH - acidic
Significance:
• 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:
• Quinine
• colchicine
• d-tubocurarine
• corticosteroids
• erythromycin
Biliary Clearance = Biliary excretion rate
Plasma drug conc.

ENTEROHEPATIC CIRCULATION
• A drug can be recycled between the gut lumen,
hepatic portal vein, liver, bile and back to the gut
lumen;
• 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
circulation.

FAECAL ELIMINATION
• Orally ingested drugs - not absorbed throughout the gut
• Examples
1. Magnesium sulfate
2. Streptomycin
3. Neomycin
4. Bacitracin
5. Cholestyramine
6. Laxatives

ALVEOLAR EXCRETION
• Gases and volatile liquids - breath
• Excretion depends on partial pressure of the gaseous drug in the blood, not on lipid
solubility
• 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:
1. Chloramphenicol
2. Tetracyclines
3. Morphine
4. Metronidazole
5. Cytotoxic drugs
6. Diazepam
7. Oral contraceptives
8. Anti-histamines
9. Purgatives
10. Carbimazole
• Non electrolytes:
Ethanol, urea - independent of milk pH.
• Acidic drugs secreted
1. Sulfonamides
2. Penicillins
3. Ampicillin
4. Dapsone
5. Phenobarbitone
6. Theophylline

DRUGS TO BE AVOIDED IN LACTATING MOTHER
• Chloramphenicol
• Chloroquine
• Primaquine
• quinine
• Procainamide
• Nitrofurantoin
• Nalidixic acid
• Dapsone
• Isoniazid
• Probenicid
• Sulfonamides

EXCRETION VIA SKIN, HAIR, SWEAT AND SALIVA
• Keratin precursor cells - Griseofulvin
• Hair follicles - Arsenic, mercury salts, iodides
• Saliva - Phenytoin, lithium, iodine, potassium iodide, Metronidazole, Disulfiram,
Metoclopramide, Clarithromycin
• Sweat - Amines & urea derivatives, Iodides, rifamipicin, heavy metals.

SUMMARISE

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
1. Age
2. Sex
3. Species
4. Race
5. Genetic variation
6. Nutrition and diet
7. Pregnancy
8. Thyroid imbalance
9. Temporal factors
10. Diseases
11. Drug-Drug interactions - Enzyme induction / inhibition

FACTORS AFFECTING DRUG METABOLISM
1. AGE:
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
2. SEX:
Males - ↑ BMR - efficient metabolism - salicylates, alcohol, propranolol and
benzodiazepines.

FACTORS AFFECTING DRUG METABOLISM
3. SPECIES
Atropine metabolism - Rabbits > Man
4. RACE
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.

FACTORS AFFECTING DRUG METABOLISM
6. GENETIC VARIATION

FACTORS AFFECTING DRUG METABOLISM
7. PREGNANCY
CYP2D6, CYP3A4, CYP2B6, and CYP2C9 increase.
Phenytoin, midazolam, metoprolol - short t1/2
CYP1A2 and CYP2C19 decrease. (Caffiene - reduced metabolism)
UGT-1A4 - ↑
N-acetyl Transferase - ↓
8. THYROID IMBALANCE
Hypothyroidism - ↓ Elimination of many drugs. Eg - Propranolol, digoxin, etc
Hyperthyroidism - ↑ Metabolism. Eg - Low dose of warfarin is enough - increased turnover
of Vit K dependent clotting factors.
9. TEMPORAL FACTORS
Enzyme actions - ↑ in early morning

FACTORS AFFECTING DRUG METABOLISM
10. DISEASE STATES

KINETICS OF METABOLISM
Terminologies:
• 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
 First order
 Zero order
 Mixed order kinetics

PLASMA T1/2
• 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

FACTORS AFFECTING PLASMA HALF LIFE

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.

KINETICS OF ELIMINATION

FIRST ORDER KINETICS

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
drug.
• 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

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
SATURATION KINETICS
• 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

REFERENCES
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