Short Notes of Biopharmaceutics for
PPSC
BY
ANEEZA AMJAD
PPSC BATCH 442/2019,
MERIT NO: 09
Pharmacokinetic models -------
a.Compartment model, b.non-compartment model, c. physiological models
Compartment models
Body composed of different compartments/tissues with similar blood flow and drug
affinity
Types of compartment model
a. Mammillary model b.caternary models c. open models d. closed
model
1)mammillary model--- consist of one or more peripheral tissue attached with central
tissue
Central compartment is blood
One compartment model
One Compartments open model classification
a. i/v one compartment open model b. extravascular one compartment open model
1) iv one compartment open model
Only Elimination ----K1
the first order process with first order rate constant
Parameters are 3---- elimination half life, elimination ate constant, clearance
2) extravascular one compartment open model
Absorption + elimination
First order + zero order process
Parameters --- clearance, t1/2, tmax, cmax, ka, ke, f( fraction of dose)
Two compartment open model
Consist of 2 compartments
a. iv two compartment open model b. extravascular two compartment open model
1) iv two compartment model
Absorption + elimination
Parameters –ka, ke, t1/2, clearance, tmax, cmax
2) extravascular two compartment open model
Absorption + distribution + elimination
Parameters –ka,ke, vd, t1/2, clearance, tmax, cmax,
Determination of absorption rate
a. residual method b. wagner nelson method
Slope-------- -Ke/2.303
Clearance----it relates plasma drug conc. With rate of elimination, dx/dt/c
Half life---- time for decline of l conc. To 50% of original conc. T1/2= 0.693/k
Steady state conc.( Css)------conc. Of drug plasma reached at constant
value, straight line graph
Css= infusion rate/clearance=-KeT/2.303
Shorter half life sooner steady conc., 90% for therapeutic dose
Urinary excretion models ----determine excretion rate constant and
elimination rate constant
Parameters ----- AUC, Emax, Tmax, Cl, Ke, Cmax
BCS biopharmaceutical classification system
Solubility permeability
Class1 high high complete bioavailability, immediate relase
drugs
Class 2 low high bioavailability is controlled by dosage form
Class3 high low bioavailability incomplete
Class4 low low difficult to form
Bioavailability – the rate and extent of therapeutic active drug that reach the systemic
circulation and available at the site of action. AUC/Dose
Absolute bioavailability—the systemic bioavailability of oral compared with iv—
F= AUC extra / AUC iv x Dose iv/Dose extravascular
Relative bioavailability—the systemic bioavailability of oral compared with standard..
F = AUC extra1/AUC extra2 x dose extra2/dose extra1
Method of bioavailability determination —
a)pharmacokinetic method(indirect) ----blood analysis, urinary excretion method
b)pharmacodynamic method (direct)-- acute pharmacological response, therapeutic
method
AUC determination--- Trapezoidal method---AUC= ½(c1+c2)(t2-t1)+1/2(c2+c3)(t3-
t2)……
Bioequivalence --pharmaceutical equivalent or alternative products that display
comparable bioavailability
Pharmaceutical alternatives ---drug that contain same therapeutic moiety
but as different salts,esters etc. Ex.tetracycline Ph. And teteacycline Hcl
Pharmaceutical equivalent—drug products with same active ingredient
and same salts, dosage form but differ in shape , packaging, release mechanism. Ex.
Chlordiazepoxide hcl 5mg cap
Therapeutic alternatives ---drug with different active ingredient indicated for
same therapeutic or clinical objective. Ex. Cimetidine and rantidine
Therapeutic equivalent---drug product that are pharmaceutical equivalent
and same clinical object. Ex.valium and vintage (same generic )
Therapeutic substitution —the process of dispensing a therapeutic
alternative instead of prescribed drug ex. Amoxicillin instead of ampicillin
Dissolution rate--- The dissolution rate is a measure of the actual release rate
of the compound at the given particle size etc. in an aqueous media
Dissolution apparatus—
1.rotating basket apparatus
2.peddle apparatus
3.reciprocating cylinder apparatus
4.flow through cell
5.peddle over disk
6.rotating cylinder
7.reciprocating disk apparatus
Noyes whitney equation for dissolution rate; dc/dt=k(Cs-Cb)
Cs:conc.of solution at solid surface Cb: conc. Of bulk
General equation of straight line; y=mx+b slope=y2-y1/x2-x1
m=slope, b=y-intercept , y=y-axix parameter, x=x-axis parameter
Volume of distribution---hypothetical volume of body into which drug is
distributed
Vd=dose/Cp
Rate of reaction —no. of drug molecules converted into products
change in conc./change in time
order of reaction—no. of molecules whose conc. Determine rate of reaction
zero order reaction—independent of conc.
First order reaction—depends upon conc.
Protein binding—drug interact with plasma or tissue protein and form drug-
protein complex.
1.plasma protein binding-Ex albumin, globulin, fibrinogen, thrombin
2.tissue protein binding---lipoproteins
Irreversible Protein Binding= result of chemical reaction, attached strongly to drug
Reversible Protein Binding= drug binds the protein with weaker bond. It includes
Albumin, Globulin, alpha 1 glycoacid protein.
Acidic drugs bind to ALBUMIN such as Penicillins, Phenylbutazone, salicylate etc.
basic drugs bind to a1-acid glycoprotein also known as Orosomucoid. Example
Propranolol, lidocaine, imipramine etc.
globulins responsible for transportation of endogenous substances such as
corticosteroid.
Kinetics of Protein binding
r=moles of drug bound / total moles of protein
r= (PD) / (PD) +(P)
Linear pharmacokinetics non-linear pharmacokinetics
1.dose independent dose independent
2.ADME follow 1st order Saturable
3.AUC directly proportional to dose AUC is disproportional to dose
4.PK parameters constant PK parameters dose dependent
5.conc vs time superimposeable not superimposeable
Michelis menton equation for non-linear PK;
v=Vmax(S)/Km+(S)
V=rate of metabolism,
Vmax=max. rate of met.
S=substrate conc.
Km=mechalis constant
IVIVC in-vitro in-vivo correlation—relationship b/w in-vitro property
and in-vivo response
Drug Absorption
Passage of drug across cell membrane
1)Passive Diffusion: Spontaneous diffusion from area of higher conc. To lower conc.
No external energy required
Fick’s law:Dq/dt=DAK/h(C GI-CP)
Dq/dt=rate of diffusion, D=diffusion co-efficient
K= lipid-water partition co-efficient A=surface area
H=memb. Thickness CGI -CP=difference b/w conc.
2)Active Diffusion: Carrier mediated transmembrane process from region of low conc.
To high conc. Energy consuming process
3)Facilitated diffusion: carrier mediated diffusion move along conc. Gradient. It is
saturable.
Vesicular transport=processof engulfing particles by the cell.
1)Pinocytosis: engulfment of small solutes
2)Phagocytosis:engulfment of larger paarticles
3)Endocytosis: process of moving specific molecules into the cell.
4)Exocytosis: process of moving specific molecules out of the cell.E.g.transport of
Insulin
5)Transcytosis:process by which various macromolecules are transported into the
interior of cell.
Drug Elimination and Hepatic Clearance
Drugs eliminate from body involves the proceessof both metabolism
1)Biotransformation=enzymatic conversion of a drug to a metabolite. E.g.
Theophylline, Phenytoin, Acetaminophen etc. Follow the Michalis-Menten equation
Michelis menton equation for non-linear PK;
v=Vmax(S)/Km+(S)
V=rate of metabolism,
Vmax=max. rate of metabolism.
S=substrate conc.
Km=mechalis constant
Relation of Rate of metabolism to Drug conc. Is non-linear and curve is hyperbolic.
Phase I Reaction: occur first and introduce a functional group on drug molecule.
Oxidation: Addition of oxygen.Aromatic Hydroxylation, Deamination, Sulfoxidation, N-
Hydroxylation
Reduction: Addition of Hydrogen. Azoreduction, Nitro-reduction, Alcohol
dehydrogenase
Hydrolysis: addition of H2O and cleavage of bond. Ester hydrolysis, Amide hydrolysis
Phase II Reaction/ Conjugation: once a polar constitute is placed, conjugation
reaction may occur. Involve conjugating agents ,High energy intermediates
formed which combined with drug to form conjugate.
Conjugation Conjugating agent High-energy Functional groups
reaction intermediate combined with
Gulcuronidation Glucuronic acid UDPGA _OH, _COOH
Sulfation Sulfuric acid PAPS _NH2, _SH
Acetylation Acetyl Co A Acetyl Co A _OH, _NH2
Methylation CH3 S-adenosyl _OH, _NH2
methionine
Glutathione Glutathione Epoxide, Epoxide
2)Renal Excretion=drug disposition by the kidney include glomerular filtration,
active tubular secretion etc.
Hepatic Clearance=volume of blood that perfuse the liver which is cleared of drug
per unit time.
Clh=CIT+CIR CIh=Hepatic clearance, CIT=total clearance CIR= renal
clearance
FIRST-PASS EFFECT=Rapid metabolism of an orally administered drug before
reaching the general circulation.
Absolute Bioavailability=F= AUC oral / Doral
AUC iv / D iv
Drugs 100% absorbed and stable in GIT, Absolute Bioavailability=F=1
Drugs undergo first-pass effect, F>1 EXAMPLE; Nitroglycerin, Morphine
Multiple-Drug Oral Dose Regimen
Drug conc. After multiple oral dose
Cav=FD0/VDKᴫ
ᴫ=dosage interval, F=fraction of dose absorbed
Cmax=FD0 ⌠1/1-e-kᴫ ⌡e-ktp
VD
Cmax=kaFD0 ⌠1/1-e-kᴫ ⌡e-kt
VD (ka-k)
