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ERT 420 BIOPHARMACEUTICAL ENGINEERING Semester 1 Academic Session 2012/2013. HUZAIRY HASSAN School Of Bioprocess Engineering Universiti Malaysia Perlis. DRUG BIOAVAILABILTY & BIOEQUIVALENCE. Drug Absorption & Bioavailability.
School Of Bioprocess Engineering
Universiti Malaysia Perlis
Absorption is the rate and extent at which drugs reach the systemic circulation from the site of administration.
Distribution of drugs includes all the processes involved from the time when the drugs reaches the circulation to the time when it (or drug metabolite) leaves the body.
Metabolism involves all biochemical processes resulted in a chemical change to the drug compound including both the metabolism in the gut wall, the liver, and blood circulation.
Excretion is the process in which the drug is eliminated from the systemic circulation into bile, urine, feces, sweat, and air.
Bioavailability (BA): rate and extent to which API or active moiety is absorbed from a drug product and becomes available at the site of action.
F = Fa x Fg x Fh
Fraction that escapes first
pass hepatic metabolism
*Fraction of drug absorbed
Fraction that escapes metabolism in GI tract
Oral drug absorption process occurs mainly in small intestinal regions, including passive transcellular diffusion, carrier-mediated transport processes, paracellular transport, and endocytosis.
Lipophilic compounds- absorbed by passive diffusion
Hydrophilic compounds- absorbed through carrier-mediated process
Some small hydrophilic compounds – may be transported through paracellular junction
IMT includes paracellular and transcellular transports.
Can be divided into passive diffusion, endocytosis, and carrier-mediated transport.
Passage of solute without passage through the epithelium cells
- hydrophobic molecules can pass through the lipid bilayers by random molecular motions.
- mass transfer of molecules depends on the concentration gradient on the 2 sides of membrane.
- governed by Fick’s first law of diffusion.
M = drug mass (g, mol)
A = surface area (cm2)
t = time (s)
D = diffusion coefficient (diffusivity, cm2s-1)
C1 = drug concentration at membrane wall in intestinal lumen (mol L-1)
C2 = drug concentration at membrane wall in blood side (mol L-1)
h = membrane thickness (cm)
Define partition coefficient, K
K = C1 /Cd= C2 / Cr
Cd: drug concentration in the GI lumen
Cr : drug concentration in the blood
K: Partition coefficient (measure of substance solubility in lipid)
D: Diffusion coefficient (depends on MWor size of molecule)
h: thickness of cell membrane
Therefore, P is related to membrane and drug properties. For specific drug, the passive membrane permeability should be a constant Pm and independentto drug concentration.
Jmax: Maximum drug flux
Km: Drug affinity to carrier
Therefore, Total Effective Permeability:
- The drug molecules have to be dissolved in the solution for the absorption to occur in intestinal tract.
* For weak basic drugs, more unionized form would be predominant in intestine at high pH (5-8) favors absorption.
* For weak acid drugs, more ionized form in intestine.
* Ionized form is more water soluble than unionized.
* Unionized form is easier for absorption by passive diffusion.
Federal regulations (21 CFR, 2006) define Bioequivalence as:
The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
Equivalence: Relationship in terms of bioavailability, therapeutic response, or a set of established standards of one drug product to another.
Bioequivalent drug products:
describes pharmaceutical equivalent or pharmaceutical alternatives products that display comparable bioavailability when studied under similar experimental conditions.
- For systemically absorbed drugs, the test and reference listed drug, RLD (brand-name) shall be considered bioequivalent if:
a) the rate & extent of absorption of the test drug do not show significant difference from the rate & extent of absorption of the reference drug when administered at the same molar dose under similar experimental conditions in either single or multiple doses;
b) the difference from the reference drug in the rate of drug absorption is intentional, is reflected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use.
Bioequivalent drug products may contain different inactive ingredients, provided the manufacturer identifies the differences and provides information that the differences do not affect the safety or efficacy of the product.
(ex: chlordiazepoxide hydrochloride, 5-mg capsules),
but, may differ in characteristics such as shape, scoring configuration, release mechanism, packaging, excipients ( including color, flavors, preservatives), expiration time, and within certain limit, labeling.
When applicable, PE must meet the same content uniformity, disintegration time, and/or dissolution rates.
Class I : High Solubility – High Permeability
Class II : Low Solubility – High Permeability
Class III: High Solubility – Low Permeability
Class IV: Low Solubility – Low Permeability