Pharmacology ADME

Manipal College of Pharmaceutical Sciences
26-Aug-18
Pharmacology: ADME
Dr Yogendra Nayak
yogendra.nayak@manipal.edu; yogendranayak@gmail.com
Mobile: 9448154003

Manipal College of Pharmaceutical Sciences - MAHE Manipal 2
What are Medicines/ Drugs?
• What is a drug/ drugs?
• What is Pharmacology?
• What is Pharmacotherapy, Clinical Pharmacology,
Chemotherapy, Toxicology?

Introduction
• Pharmacokinetics
– What body does to the drugs
• Pharmacodynamics
– What drugs does to the body

Pharmacokinetics - A D M E
• Absorption
• Distribution
• Metabolism
• Elimination

Routes of Drug Administration
• Local route (Topical)
• Systemic route

Oral Route

Sublingual/ Buccal

Rectal

Urethral/
Vaginal

Cutaneous/ Transdermal

Dermojet Iontophoresis

Implants

Topical
Eye drops
Eye ointments

Inhalation /
Nasal

Subcutaneous

Intramuscular

Cite of IM Injections
• Deltoid
• Dorsogluteal
• Ventrogluteal
• Rectus femoris
• Vastus lateralis

Intravenous

Intra-articular

Intrathecal

Pharmaceutics 2018, 10, 10; doi:10.3390/pharmaceutics10010010

• Systemic route
– Enteral
– Mucus Membrane
• Sublingual/ buccal
• Ocular/ Eye drops/ Ear drops
• Pulmonary & Nasal
• Rectal, vaginal & Urethral etc.
– Cutaneous/ Transdermal
– Parenteral (Par-beyond, enteral-intestinal)

• Parenteral (Par-beyond, enteral-intestinal)
– Subcutaneous (s.c.)
– Intramuscular (i.m.)
– Intravenous (i.v.)
– Intradermal injection

• Parenteral (Par-beyond, enteral-intestinal)
– Intrathecal
– Intra-arterial
– Intra-articular
– Epidural

Barriers
• Cell Membrane Barrier
• Blood Brain Barrier (BBB)
• Blood Cerebrospinal Fluid Barrier
• Blood Placental Barrier
• Blood Testis Barrier … Etc.

Thalidomide Tragedy

Factors Regulating Absorption of Drugs
• Aqueous solubility/ Lipid solubility
• Concentration gradient/ Particle size/
Disintegration/ Dissolution
• Absorption area
• Absorbing surface vascularity
• pH of the media/ GIT/ Ionisation of drugs
• Route of administration

Different Mechanism of Drug Absorption
• Passive transport
– Diffusion
• Simple diffusion
• Facilitated diffusion
– Osmosis: Aquaporins
• Active transport
– Energy is required for this process
– Primary & secondary active transport mechanism
• Vesicular transport
– Endocytosis
• Receptor mediated endocytosis
• Phagocytosis
• Bulk phase endocytosis (pinocytosis)
– Exocytosis
– Transcytosis: Placental circulation of antibody from mother to
fetus

Passive Diffusion
• Lipid solubility of drugs
– General Anaesthetic gases
– Local anaesthetics
– CNS drugs – sedative hypnotics/ anticonvulsants etc

Passive Diffusion: Influence of pH
• A. Dissociation of a weak acid, pKa = 4.4
• B. Weak acid in plasma (pH 7.4) &
Gastric acid (pH 1.4)
• Aspirin at Gastric region &
Atropine at small intestine
• Chlordiazepoxide
• Second generation H1 receptor
antagonists

Glucose
transporter
Glucose
gradient
Glucose
Extracellular fluid Plasma membrane Cytosol
1
Glucose
transporter
Glucose
gradient
Glucose
1
2
Glucose
transporter
Glucose
gradient
Glucose
Glucose
1
2
3

Absorption: Facilitated Diffusion
• Solute Carrier (SLC) Transporters
• Concentration gradient
• Glucose

Membrane Transport Mechanisms

Active Transport of Drugs
• ATP Binding Cassette (ABC) Transporters
• Na+,K+-ATPase  Digoxin
• P-glycoprotein encoded  Multidrug
resistance-1 (MDR1) gene

Membrane Transporters
• ATP Binding Cassette (ABC)
Transporters
• SLC (solute carrier) transporters
• Organic anion-transporting polypeptide OATP1B1 in
liver  Pravastatin  reduced systemic toxicity
• Organic cation transporters (OCT1 & OCT2) 
Substrate ‘cephaloridine’  nephrotoxicity
SLCABC

Distribution
• Drug distribute after absorption
• Factors affecting distribution
– Tissue Affinity
– O/W ration [Partition coefficient/ lipid solubility]
– pKa
– Plasma protein binding
– Blood flow
– Disease states
– Gender & Age

Distribution
• Apparent volume of distribution (aVd)
– “Volume that would accommodate all the drug
in the body, if the concentration throughout was
the same as in plasma"

Transporters in Pharmacokinetic Pathways

Hepatic Drug Transporters

SLC Gene Proteins
• SLC3/ 7 (amino acid transporter): Melphalan
• SLC5 (Na+ glucose cotransporter): Dapagliflozin
• SLC6 (Na+- & Cl– - dependent neurotransmitter transporter):
Paraoxetine, fluoxetine
• SLC9 (Na+/H+ exchanger): Thazide diuretics
• SLC10 (Na+ bile salt cotransporter) : Benzothiazepines
• SLC16 (Monocarboxylate transporter): Benzothiazepines
• SLC16 (Monocarboxylate transporter): Pravastatin, metformin
• SLC26 (Multifunctional anion exchanger): Salicylic acid, ciprofloxacin
• SLC29 (Facilitative nucleoside transporter): Dipyridamole, gemcitabine
• SLC31 (Copper transporter): Cisplatin

MDR1 (ABCB1) Transporters
• Location: Liver, Kidney, Intestine, BBB, BTB, BPB
– Anticancer drugs: etoposide, doxorubicin, vincristine
– Ca2+ channel blockers: diltiazem, verapamil
– HIV protease inhibitors: indinavir, ritonavir
– Antibiotics/Antifungals: erythromycin, ketoconazole
– Hormones: testosterone, progesterone
– Immunosuppressants: cyclosporine, tacrolimus
– Others: digoxin, quinidine, fexofenadine, loperamide

MRP1 (ABCC1)
• Location: Kidney, BCSFB, BTB
– Anticancer: vincristine (with GSH), methotrexate
– Glutathione conjugates: leukotriene C4,
glutathione conjugate of ethacrynic acid
– Glucuronide conjugates: estradiol-17-D-
glucuronide, bilirubin mono(or bis)glucuronide
– Sulfated conjugates: estrone-3-sulfate (with GSH)
– HIV protease inhibitors: saquinavir
– Antibiotics: grepafloxacin
– Others: folate, GSH, oxidized glutathione

MRP2 (ABCC2)
• Location: Liver, Kidney, Intestine, BPB
– Anticancer drugs: methotrexate, vincristine
– Glutathione conjugates: leukotriene C4, glutathione
conjugate of ethacrynic acid
– Glucuronide conjugates: estradiol-17-D-glucuronide,
bilirubin mono (or bis) glucuronide
– Sulfate conjugate of bile salts: taurolithocholate
sulfate
– Amphipathic organic anions: statins, angiotensin II
receptor antagonists, temocaprilat
– HIV protease inhibitors: indinavir, ritonavir
– Others: GSH, oxidized glutathione

O/W coefficient [Partition coefficient/ lipid solubility]
logP =
Drug[Octanol]
Drug[Water]log

Distribution
• Plasma protein binding
– Estrogen or Testosterone  sex hormone–binding
globulin
– Thyroxine  thyroxin-binding globulin
• Tissue binding
– Quinacrine  Liver; Thyroid  Iodine
• Fat as reservoir
– Thiopental 70% dose in fat of obese

Distribution
• Bone
– Etidronate
• Redistribution
– Thiopental sodium  short duration of action
• CNS and Cerebrospinal Fluid
– 2nd gen antihistamines  Loratadine lower brain
concentrations than  diphenhydramine
• Placental Transfer of Drugs  Thalidomide

Plasma Protein Binding
• Acidic/ Neutral drugs 
Albumin
• Basic drugs  α1 acid
glycoprotein

• Acidic/ Neutral drugs 
Albumin
– Barbiturates
– Benzodiazepines
– NSAIDs
– Valproic acid
– Phenytoin
– Penicillins
– Sulfonamides
– Tetracyclines
– Tolbutamide
– Warfarin

• Basic drugs  α1 acid
glycoprotein
– β-blockers
– Bupivacaine
– Lidocaine
– Disopyramide
– Imipramine
– Methadone
– Prazosin
– Quinidine
– Verapamil

Clinically Implications of Plasma Protein Binding (PPB)
• Highly PPB  vascular compartment  ↓ Vd
• PPB Acts as temporary storage site
• Highly PPB  ↓ metabolism/excretion  ↑ duration of
action
• Plasma level of drug = plasma free drug + protein bound
drug  cannot relate the effect!

Clinically Implications of Plasma Protein Binding (PPB)
• Drug-drug interaction  Competing for binding  Toxicities
– Eg., Salicylates  Sulfonylurea
– Indomethacin/ Phenytoin  Warfarin
• High PPB  Haemodialysis
• Hypoalbuminemia  ↑ Free drug  Toxicity
• Some disease/ pregnancy  Alter binding

[F] Bioavailability (L) =
Quantity of Drug at Cite of Action
≈ Plasma/ Serum (g/L)
Quantity of Drug Administered (g)
Dose = Quantity of Drug Administered (g)

Factors Affecting Absorption & Bioavailability
• Physico-chemical Properties of Drugs
– Drug solubility & dissolution rate
– Particle size
– Lipophilicity of drug
– pKa of drug
– Salt form of drug
• Dosage form Characteristics
– Disintegration time
– Dissolution time
– Pharmaceutical variables
– Nature and type of dosage form
– Manufacturing variables

Factors Affecting Absorption & Bioavailability
• Pharmacological Factors
– Age
– Gastric emptying
– Intestinal transit time
– Gastrointestinal pH
– Disease states
– Blood flow through GIT
– GI contents
– Presystemic metabolism

PlasmaConcentration
Time (h)
Drug-Concentration-Time Profile
AUC
Minimum effective
Concentration
Minimum Toxic
Concentration
Bioavailability = AUC

PlasmaConcentration
Time (h)
Drug-Concentration-Time Profile after Oral Administration
AUC
Minimum effective
Concentration
Minimum Toxic
Concentration
Onset of
Action
Duration
of Action

PlasmaConcentration
Time (h)
Minimum effective
concentration
A
B C
Drug-Concentration-Time Profile by Different Drugs

PlasmaConcentration
Time (h)
Minimum effective
concentration
Oral
I.V.
Drug-Concentration-Time Profile by Different Route of Administration
I.M.

PlasmaConcentration
Time (h)
Minimum effective
concentration
I.V. Bolus
Drug-Concentration-Time Profile by I.V. Bolus & I.V. Infusion
I.V. Infusion
Stop

PlasmaConcentration
Time (h)
Time Course of Drug in Each Compartment
Drug at
Abs Site
Plasma
Drug
Metabolite
Excreted drug

Drugs After Absorption - 3 Possible Fates
• Metabolic transformation by enzymes
– Active drug to inactive metabolite
– Inactive (Prodrug) drug to active drug
– Active drug to active metabolite
• Spontaneous structural change
– e.g. Atracurium (Hofmann elimination)
• Excretion unchanged
– e.g.. Aminoglycosides (streptomycin), pancuronium

Metabolism

Metabolism
Inactivation

Metabolism
Active metabolite from active drug

Metabolism
Active metabolite from inactive drug  Prodrug

Metabolism - Biotransformation
• Nonsynthetic / Phase 1 metabolism
– Oxidation
– Reduction
– Hydrolysis
– Cyclisation
– Decyclisation
• Synthetic / Phase 2 metabolism
– Glucuronide conjugation
– Acetylation
– Methylation
– Sulfate conjugation
– Glycine conjugation
– Glutathione conjugation
– Ribonucleoside/ nucleotide synthesis

• N-Dealkylation RNHCH3  RNH2 + CH2O
– Imipramine, diazepam, codeine, erythromycin, morphine,
tamoxifen, theophylline, caffeine
• O-Dealkylation ROCH3  ROH + CH2O
– Codeine, indomethacin, dextromethorphan
• Aliphatic hydroxylation RCH2CH3  RCHOHCH3
– Tolbutamide, ibuprofen, phenobarbital, meprobamate,
cyclosporine, midazolam
Biotransformation: Oxidative Reactions

Biotransformation: Oxidative Reactions
• Aromatic hydroxylation
– Phenytoin, phenobarbital, propanolol,
ethinyl estradiol, amphetamine, warfarin
• N-Oxidation
– Chlorpheniramine, dapsone, meperidine
• S-Oxidation
– Cimetidine, chlorpromazine, thioridazine,
omeprazole
• Deamination
– Diazepam, amphetamine

Biotransformation: Hydroxylation
• Carbamazepine, Procaine, Aspirin,
Clofibrate, Meperidine, Enalapril, Cocaine,
Lidocaine, Procainamide, Indomethacin
Carbamazepine

Biotransformation: Cyclisation & Decyclisation
• Cyclisation
– Proguanil
• Decyclisation
– Barbiturates, phenytoin

• Glucuronidation
– Acetaminophen, morphine, oxazepam,
lorazepam
• Sulfation
– Acetaminophen, steroids, methyldopa
Biotransformation: Conjugation

Biotransformation: Conjugation
• Acetylation
– Sulfonamides, isoniazid, dapsone, clonazepam
• Methylation
– L-Dopa, methyldopa, mercaptopurine, captopril
• Glutathionylation
– Adriamycin, fosfomycin, busulfan

Enzymes in Biotransformation
• Microsomal enzymes
– Smooth endoplasmic reticulum in cells of liver,
intestine, kidney, lungs
– Monooxygenases, CYP, Glucuronyl transferase
• Non microsomal enzymes
– Cytoplasm, mitochondria, hepatic cells, plasma
– Flavoprotein oxidases, esterases, amidases,
conugases etc
– Not inducible, but genetic polymopphism are seen

Enzymes in Biotransformation – Enzyme Location

Biotransformation: Cytochrome P450 (CYP)
• Cytochrome P450 enzymes
– <100 CYP isoenzymes
– CYP 1, 2 & 3 Families
– CYP sub families with alphabetical A, B, C etc…
• CYP3A3,4/5  largest ≈50% drug metabolism
• CYP2D6  ≈20%
• CYP2E1 is for Alcohol metabolism

Biotransformation – Enzyme Inhibition
• One drug can competitively inhibit the
metabolism of other
– Direct & Indirect inhibition
• Competitive inhibition: Methacholine & ACh
• Non-competitive inhibition: Isoniazid & Phenytoin;
organophosphorus compounds inhibiting
cholinesterase
• Product inhibition: Allopurinol  oxypurinol,
inhibiting xanthine oxidase

Biotransformation – Enzyme Inhibition
• Allopurinol
• Omeprazole
• Erythromycin
• Clarithromycin
• Chloramphenicol
• Ketoconazole
• Itraconazole
• Metronidazole
• Ciprofloxacin
• Sulfonamides
• Fluoxetine (& SSRIs)
• Diltiazem
• Amiodarone
• Propoxyphene
• Isoniazid
• Cimetidine
• Quinidine
• Disulfiram
• Verapamil
• MAO inhibitors
• Ritonavir (& other HIV
protease inhibitors)

Biotransformation – Enzyme Induction
• Enzyme induction
– DNA interaction to increase production of
enzymes
– Alchohol, Phenobarbitone, Rifampicin,
Griseofulvin, Phenytoin
– DDT, & other pesticides
– Cigarette smoking  ↑ Elimination of
theophylline

Factors Affecting Drug Metabolism
• Age
• Disease
• Species Differences
• Heredity/ Genetics
• Sex; Pregnancy
• Environmental Factors
• Drug Dose
• Enzyme Induction
• Enzyme Inhibition
• Diet

First Pass Metabolism
• Enzymes present in Liver, Intestine etc
• May occur in skin
– Determines oral bioavailability
• Clinical Significance
– Considerably high oral dose
– Liver disease  Increased oral bioavailability
– Variation in oral dose among individuals

First Pass Metabolism, Examples
Low Intermediate High
Not given orally High oral dose
Phenobarbitone
Phenylbutazone
Tolbutamide
Theophylline
Pindolol
Isosorbide
mononitrate
Aspirin
Quinidine
Desipramine
Nortriptyline
Chlorpromazine
Pentazocine
Metoprolol
Isoprenaline
Lidocaine
Hydrocortisone
Testosterone
Propranolol
Alprenolol
Verapamil
Salbutamol
Glyceryl trinitrate
Morphine
Pethidine

Elimination
• Urine
• Faeces
• Exhaled air
• Saliva & Sweat
• Breast Milk

Species Differences

Renal Excretion
• Distinct processes
– Glomerular filtration
– Active tubular secretion
– pH dependent passive
tubular reabsorption

Glomerular Filtration (GF)
• Glomerulus  Larger pores (75-100A)
• GF depends on PPB & Renal Blood Flow
• Non protein bound drugs (lipid soluble,
insoluble) are filtered
• GFR ↓ in 50 years & above & in renal
failure

Tubular Reabsorption/ Secretion
• Passive diffusion
• Active tubular secretion
• Passive diffusion - Depends on lipid
solubility & ionization at urinary pH
• Lipid soluble, unionized drugs back diffuse –
reabsorbed
• Lipid insoluble, ionized drugs - excreted

Urinary pH Affects Tubular Reabsorption
• Basic drugs better excreted in acidic urine
– e.g. morphine, amphetamine
• Acidic drugs better excreted in alkaline urine
– e.g. barbiturates, salicylates
– Principle is utilized for facilitating elimination in
poisoning
• Drugs with pKa 5-8  greatest effect

Active Tubular Secretion
• PCT contain efflux transporter
– Luminal membrane of tubular cells
– P-glycoprotein, MRP2
• Active transport  free drug in tubular vessels
 dissociation of protein bound drugs
• Transporter
– Organic base (OATP): Penicillin, Salicylates,
Probenecid
– Organic acid (OCT): Thiazides, quinine, amiloride
– Both transport processes are bidirectional
• Drugs & metabolites  Secretion into lumen
• Endogenous substrates  uric acid, reabsorption

Transporter Affinity in Tubular Filtration
• Probenecid & Penicillin  Penicillin excretion ↓
• Probenecid & Uric acid  Uric acid excretion ↑
• Tubular transportation  not well developed at birth
– ↑ duration of action  penicillin, aspirin
• Salicylates
– Block  uricosuric action of probenecid & Sulfinpyrazone
– Decrease tubular secretion of methotrexate.
• Probenecid
– ↓ nitrofurantoin in urine
– ↑ duration of action of penicillin/ ampicillin
– Impairs secretion of methotrexate
• Sulfinpyrazone inhibits  tolbutamide
• Quinidine ↓ renal & biliary clearance of digoxin by
inhibiting P-gp

Drugs Excretion: Other Routes
• Liver actively transports into bile the organic
acids (drug glucuronides), organic bases
– Larger molecules (MW>300) are eliminated in
bile
– Enterohepatic cycling - ultimate excretion in urine
– Unabsorbed drugs, its metabolites in bile are
excreted in faeces
• Drugs excreted directly into colon  Senna,
heavy metals
• Lungs : exhaled air  GA, Volatile liquids
etc. irrespective of their lipid solubility

Drugs Excretion: Other Routes
• Sweat & saliva  Lithium , KI, Rifampin,
heavy metals
• Milk- is slightly acidic, (pH -7 ) than
plasma. Basic drugs gets excreted by
passive diffusion
– More lipid soluble & less protein bound drugs
are excreted
– Small amount transferred to Suckling infant
– So drugs are prescribed to lactating mothers
when absolutely necessary

Elimination Kinetics
• Fundamentals of
Pharmacokinetics
– Bioavailability (F)
– Volume of distribution (V)
– Clearance (CL)

PlasmaConcentration
Time (h)
AUC
Minimum effective
Concentration
Minimum Toxic
Concentration
Onset of
Action
Duration
of Action
Therapeutic
Window
Desired Response
Adverse Response
Side effects
Sub-therapeutic effects
kabs kexc

PlasmaConcentration
Time (h)
Therapeutic
Window
Side effects
Sub-therapeutic effects
kabs kexc

• CL = Rate of elimination/ C

• First order (exponential) kinetics
– kel is directly proportional to C
– CL remains constant or a constant
fraction present in the body is
eliminated in unit time
• Zero order (linear) kinetics
– kel remains constant irrespective of C
– CL decreases with increase in C; or
a constant amount is eliminated in
unit time, eg: Ethyl alcohol

• First order (exponential) kinetics

• Plasma half-life (t½)
– Definition: time taken for its plasma
concentration to be reduced to half
of its original
– t½ = [Natural log 2] / kel
– t½ = [0.639/kel ]
– But, kel = [CL / V] – by definition
– t½ = [0.639 X V] / CL

• Plasma half-life (t½) implications
– Complete elimination in 4-5 half
lives
– First order kinetics t½ remains
constant  V & CL do not change
with dose
– Zero order kinetics - t½ increases
with dose  CL progressively
decreases as dose is increased

• Plasma half-life (t½) - Examples
– Aspirin  4 hr
– Penicillin-G  30 min
– Doxycycline  20 hr
– Digoxin  40 hr
– Digitoxin  7 days
– Phenobarbitone  90 hr

• Repeated drug administration
– Drug accumulates in the body till Elimination = intake
– Steady State Plasma concentration (Cpss) = [ Dose rate ] / CL
– Dose rate = Target Cpss x CL ---  [for i.v route]
– Dose rate = [Target Cpss X CL ] / F ---  [for oral route]

• First order (exponential) kinetics &
Zero order kinetics

Plateau Principle

• Loading dose
– Single or few quickly repeated doses given to attain target
concentration rapidly
– Loading dose = [ Cp X V ] / F
– Governed by V & not by CL or t½

• Maintenance dose
– Dose that is repeated at uniform intervals after attainment of
target Cpss to maintain the same by balancing elimination rate
– Dose rate = [ Target Cpss X CL ] / F
– Governed by CL and t½ of the drug

• Monitoring of plasma concentration of drugs
– Therapeutic drug monitoring (TDM)
1. Drugs with low margin of safety  Digoxin, anticonvulsants,
antiarrhythmics, theophylline, aminoglycoside antibiotics, lithium,
tricyclic antidepressants
2. Large individual variations  Antidepressants, lithium
3. Potentially toxic drugs used in presence of renal failure 
aminoglycoside antibiotics, vancomycinIn
4. Poisoning
5. Failure of response without any apparent reason  antimicrobials
6. To check patient compliance  psychopharmacological agents

Pharmacokinetics of Prolonging Drug Actions
• Advantages
1. Reduces Frequency of administration
2. Improved patient compliance
3. Plasma level fluctuations are avoided  Less side
effects
4. Drug effect could be maintained overnight without
disturbing sleep, e.g. antiasthmatics, anticonvulsants,
etc.

Methods of Prolonging Drug Actions
• Prolonging absorption
– Oral Route of administration
• Sustained release/ Controlled release
• Coated tablets/ Enteric coated
• Usage of semipermeable membrane in formulations

– Parenteral
• Parenteral depot (for i.m. and s.c.)
• Pellet implantation
• Sialistic preparation
• Addition of vasoconstrictor/ nerve block

– Transdermal
• Patches
• Strips
• Ointments etc.

• Increasing plasma protein binding
– Drug Congeners
• Sulfadoxine

• Retarding rate of metabolism
– Allopurinol inhibits metabolism of
mercaptopurine
– Ethinyl group addition to estradiol

• Retarding renal excretion
– Probenecid prolongs action of penicillin &
ampicilliin

Manipal College of Pharmaceutical Sciences 141
Thank you
Ph: 9448154003
yogendra.nayak@manipal.edu; yogendranayak@gmail.com

Pharmacology ADME

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Pharmacology ADME

Similar to Pharmacology ADME (20)

Recently uploaded

Recently uploaded (20)

Pharmacology ADME

Editor's Notes