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Bioavailabilitas dan Interaksi

Nurina Hasanatuludhhiyah dr., M.Si
• Zaman N. 2009. Ars Prescibendi Resep yang
Rasional. Airlangga University Press. Surabaya
• Katzung, B.G., 2012. Basic and Clinical
Pharmacology. 12th Ed. USA: McGraw-Hill
• Shargel L & Yu ABC. 2016. Applied
Biopharmaceutics and Pharmacokinetics 7th
ed.Singapore : McGraw-Hill
• Basori A. 2014. Interaksi Antar Obat. Dep
Farmakologi FK UNAIR. Surabaya
the rate and extent to which the active
ingredient or active moiety is absorbed from a
drug product and becomes available at the
site of action (US-FDA, DCER 2014a)
Time course of drug concentration
Determination of bioavailability

• = The fraction of
unchanged drug reaching
systemic circulation
following administration
by any route

• A drug given by the

intravenous route :
absolute bioavailability of 1
(F=1 or 100%

• Drugs given by other

routes usually have an

absolute bioavailability of
less than one

• ~Area under the curve (AUC)

Absolute Bioavailability
• Compares the
bioavailability of the
active drug in systemic
circulation following
administration with the
bioavailability of the
same drug following
• Fabs = AUCpo . Div
AUCiv . Dpo
Relative bioavailability
• the bioavailability of a given drug from a ‘test’
dosage form is compared to that of the same
drug administered in a ‘standard’ dosage
form, which is either an orally administered
solution (from which the drug is known to be
well absorbed) or an established commercial
preparation of proven clinical effectiveness
• Frel = 100. AUCB / DB
• The absence of a significant differences in the
rate and extent to which the active ingredient
or active moiety becomes available at the site
of drug action when administered at the same
molar dose under similar conditions in an
appropriately designed study
Factors affecting bioavailability-drug
• The Dose
• Physicochemical properties of the drug
• Dosage form
• Formulation
• Route of administration
• Excipient
Physicochemical properties of the drug
• Lipid & water solubility
• Stability
• pKa & pH profile
• Particle size
• Polymorphism
• Partition coefficient
• Chirality
Dosage form (pulveres)
Drug Formulation
Routes of administration
Factors affecting bioavailability-px
• Age, weight, body surface area
• Physiologic factors
• Occurence of certain hepatic or renal disease
• Drug interaction
• First pass effect
Physiologic factors
- pH of Stomach and intestine
- Surface area of the of the intestine – microvilli
- Presence of carrier proteins for absorption &
efflux (Pgp)
- Enzymes
- GI blood flow
- Gastric Emptying & intestinal transit
When to concern bioequivalence?
• Antimicrobials
• Anticonvulsants
• Oral antidiabetic medication
• Anticancer
• Anticoagulant
• Cardiovascular drugs
Drug product Dose (mg) AUC
Oral tablet 200 89,5
Oral solution 200 86,1
IV bolus 50 37,8

Fabs ? Frel?
Drug interaction
• The alteration of patient’s responses to drugs
by concurrent administration of other drugs,
herbals, supplements, food or beverage
Drug Interaction
• Pharmaceutical
• Pharmacokinetic
• Pharmacodynamic

Benefit HARM
Pharmaceutical drug-drug interaction
• Precipitation of Sodium Thiopentone with
Vecuronium within an intravenous set
• Mixture of Phenobarbital and water can not
be soluble
Pharmacokinetic- Absorption
• Directly, before absorption :
-- Adsorbant : Kaolin, Pectin, Charcoal
-- Anion exchange resins (Cholestyramine;
-- Chelation : Tetracyclin, Azithromycin,
Fluoroquinolone w/ divalent or trivalent
cations (Fe2+, Ca2+, Al3+) (susu)
Pharmacokinetic- Absorption
• Alteration of pH of GI tract
-- Antacid, H2 blockers, proton pump inhibitor :
reduce absorption of Ketokonazole,
Itrakonazole, Isoniazid, Indinavir, Fe2+ ,
increase absorption of Aspirin, Glibenclamide,
Pharmacokinetic- Absorption
• Alteration of gastrointestinal physiology
-- Gastric transit time :
↓Metoclopramide; Domperidon; Laxatives;
↑Anticholinergic; Opioid
-- Intestinal motility : opioid
-- Damage of intestinal mucosa : antineoplastic;
antiretroviral; NSAIDs
Pharmacokinetic- Absorption
• Alteration of active and passive transport
Ex : grape fruti juice may reduce bioavailability
of β-blockers
• P-glyprotein efflux transporter
P-glyprotein inhibitor: Ketokonazole,
Amiodarone, Quinidine, Macrolide → ↑
Pharmacokinetic- Absorption
• Alteration of intestinal normal flora : Broad
spectrum AB may ↑ effect of oral anti
• Food :
-- ↓ absorption of Penicillin; Erythromycin;
Tetracycline; Rifampicine; Captopril; Isoniazid
-- ↑ absorption of Hidrochlorotiazide; Phenytoin;
Nitrofurantoin; Albendazole
Drug-food interaction
• Pectin ↓ Paracetamol absorption
• High protein food ↓absorption of levodopa;
methyldopa; Teophyliine; Cimetidine; Sucralfate
• Fatty food ↑ absorption of Griseovulfin;
Itraconazole; Lovastatin; Spironolacton;
• Spinach; broccoli : ↓ effect of anti coagulant
• Vitamin C ↑ absorption of Fe
• Vitamin D ↑ absorption of Ca
Pharmacokinetic- distribution
• Higly protein bound drugs
• Low Vd
• Narrow margin of safety
Drug interaction-distribution
Drug B Drug A
Valproic acid Phenytoin
Phenylbutazone (89%; Vd 0,7 L/kg)
Sulphonamide Tolbutamide
(96%; Vd 0,11 L/kg)
(99%; Vd 0,14 L/kg)
Salicilic acid Bezodiazepine
Pharmacokinetic- Metabolism
• CyP450 inducer
• CyP450 inhibitor
CyP1A2 hepatic enzyme
Substrate Inducer Inhibitor
Acetaminophen Hydrocarbon Fluvoxamine
Caffeine of cigarette
Tamoxifen Hydrocarbon
Teophylline of food
Warfarin Omeprazole
CyP2C9 hepatic enzyme
Substrate Inducer Inhibitor
Celecoxib Barbiturate Phenylbutazone
Phenytoin Rifampicin Metronidazole
Ibuprofen Phenytoin
CyP3A4 hepatic enzyme
Substrate Inducer Inhibitor
Amiodarone Barbiturate Phenylbutazone
Acetaminophen Rifampicin Metronidazole
Dapsone Phenytoin
Diazepam Glucocorticoid
Ethinyl estradiol
CyP2E1 hepatic enzyme
Substrate Inducer Inhibitor
Acetaminophen Ethanol Disulfiram
Enflurane Isoniazid
• Glomerular filtration
• Secretion
• Passive reabsorption
• Additive
• Potentiation
• Synergistic - Receptor
• Antagonism - Non receptor
• Imipenem & Cilastatin (dehydropeptidase
• Penicillin & clavulanic acid; sulbactam (β-
lactamase inhibitor)
Antibiotic combination :
• Trimetoprim & Sulphametoxazole
• Penicillin & Aminoglycoside
Antihypertensive combination :
• ACE inhibitor & diuretic
Anticancer combination :
• Cyclophosphamide & Doxorubicin & 5-Fluoroacil
Triple or Quadruple Tx for eradication of H pylori
in peptic ulcer
• Antipsychotic drug with mood stabilizer
• Opioid analgesic with sedative hypnotic drug
• MAOI with tricyclic antidepressant
• Chemical : Heparin intoxication with Protamin
• Functional : amphetamine intoxication with
anti convulsant
• Dispositional : Aspirin intoxication with
sodium bicarbonate
• Receptor : Morphin intoxication with
• Intracellular receptor : Vitamin A & Vitamin D
• Transmembrane receptor :Muromonab &
Cyclosporine A
• Ion channel : Benzodiazepine & Phenobarbital
non receptor
• Interaction due to alteration of fluid &
electrolyte balance
• Interaction between drugs which work
through the same physiologic system
• Interaction due to hormonal change
• Interaction with MAO inhibitor
How to avoid drug interaction
• Thorough anamnesis & physical examination
• Avoid polypharmacy
• Special caution on : MAO inhibitor; oral
anticoagulant; oral antidiabetic drug; Digoxin;
anti cancer; anti conculsant; antihipertension;
• Give instruction to Px to not consume other
drugs or herbals without consultation
• Give instruction to Px to avoid alcohol