7/12/22

JHON RAPHAEL M. JIMENEZ, RPh, MS

Lecturer

PHARMACOKINETICS
} “What the body does to the drug”
LIBERATION- Delivery of active pharmaceutical
ingredient from a dosage form into a solution
} Study of how drugs move into, through and out
of the body including delivery to their target ABSORPTION - the drug’s uptake from the site
sites; deals with ADME of administration to the systemic circulation
DISTRIBUTION - the drug’s movement to
various sites after entering systemic
circulation
METABOLISM - the drug’s conversion to
metabolites
EXCRETION - the drug’s removal from the
body

L - Liberation
A- Absorption
a state in which any residue of the tablet,
except fragments of insoluble coating,
remaining on the screen of the test
D- Distribution apparatus in the soft mass have no
palpably firm core.

M- Metabolism
E - Excretion a process

R- Response by which a
chemical or
drug
becomes
dissolved
in a solvent

1
 7/12/22

} Development of pharmacokinetics models

that predict drug disposition after
Question? administration
◦ In vivo - involves human subjects/
laboratory animals
Does SOLUTIONS and ◦ In vitro – employs test apparatus and
equipment without involving human
PARENTERALS can undergo subjects/ laboratory animals
the LIBERATION process?

} Phospholipid: 1 head } Semi-permeable membrane, selective barrier

and 2 tails } Drugs can transport via several mechanisms
◦ Polar head attract } Protein-bound drugs (macromolecules) have
water - hydrophilic difficulty passing through

◦ Non-polar tails repel

water -hydrophobic

} Non-ionized dugs can easily pass through
than the ionized
} Low MW drugs can easily pass through than
the high MW drugs
} Lipid Bilayer/Unit Membrane Theory
◦ All the unit membranes consists of a bimolecular
layer of phospholipids covered by a layer of
proteins
} Fluid Mosaic Model
◦ States that cell membrane is made up of bi-lipid
layers and fluid protein molecules
◦ “Protein icebergs in an oily sea”
} Modified Fluid Mosaic Model
◦ Proteins are embedded and used as transport
receptors

2
 7/12/22

} Two (2) layers of phospholipids

} The polar heads stay on the outside
and the tails stay on the inside.

PRIMARY PRINCIPLES
DRUG DISSOLUTION - Rate at which solid drug enters into a Permeation
solution
The biodisposition of a drug involves its
SURFACE AREA AND PARTICLE SIZE
permeation across cellular membrane barriers.
CRYSTAL FORM/AMORPHOUS DRUG AMORPHOUS- MORE STABLE AND MORE
SOLUBLE
} Drug permeation is dependent on:
SALT FORMS SALT FORM DISSOLVE MUCH READILY
} Solubility. Ability to diffuse through lipid
COMPARED TO ITS FREE FORM bilayers (lipid solubility) is important for most
STATE OF HYDRATION ANHYDROUS IS READILY SOLUBLE VS. drugs; however, water solubility can influence
HYDRATED FORM permeation through aqueous phases.
PARTITION COEFFICIENT RATIO SOLUBILITY OF THE DRUG AT } Concentration gradient. Diffusion down a
EQUILIBRIUM IN A NON-AQUEOUS PHASE
concentration gradient-only free drug forms
POLYMORPHISM ABILITY TO EXIST IN MORE THAN ONE
CRYSTALLINE FORM
contribute to the concentration gradient.
CHIRALITY ABILITY TO EXIST AS OPTICALLY ACTIVE
} Surface area and vascularity. Important with
STERIOISOMERS OR ENANTIOMERS regard to absorption of drugs into the systemic
HYDRATES HYDRATED, SOLVATED OR ANHYDROUS circulation.

Ionization } Ionization Increases Renal Clearance of Drugs

} Many drugs are weak acids or weak bases and can
exist in either nonionized or ionized forms in an
equilibrium, depending on the pH of the
environment and their pKa (the pH at which the
molecule is 50% ionized and 50% nonionized).
} Only the nonionized (uncharged) form of a drug
crosses biomembranes.
lonized = Water soluble;
Nonionized = Lipid soluble
} The percentage of ionization is determined by the
Henderson-Hasselbalch Equation.
} Only free, unbound drug is filtered.
} Both ionized and nonionized forms of a drug are
filtered.
} Only nonionized forms undergo active secretion
and active or passive reabsorption.
} Ionized forms of drugs are "trapped" in the filtrate.
} Acidification of urineà increases ionization of
weak basesà increases renal elimination.
} Alkalinization of urine à increases ionization of
weak acids à increases renal elimination.
} To Change Urinary pH
} Acidify: NH4CI, vitamin C, cranberry juice
} Alkalinize: NaHCO3, acetazolamide

3
 7/12/22

• Partition Coefficient and Extent of

Ionization ACIDIC D + ACIDIC M = UNIONIZED
• Partition Coefficient– indication of lipid BASIC D + BASIC M = UNIONIZED
solubility of drug and its likelihood of
being transported in membrane ACIDIC D + BASIC M = IONIZED
• The Henderson-Hasselbalch equation BASIC D + ACIDIC M = IONIZED
describes the relation between the ionized
and the nonionized forms of a drug as a
function of pH and pKa
50% ionized
• pH = pKa à
50% unionized

PASSIVE Along concentration gradient, W eak organic acids, W eak organic

W ithout the use of energy bases, Organic nonelectrolytes
m ajor transm em brane process (alcohol, am idopyrine, urea),
for m ost drugs. Cardiac glycosides

Transport Mechanisms-
ACTIVE Against concentration gradient, Na, K, I, hexoses, m onosaccharides,
ü moving material in and W ith the use of energy, am ino acids, strong organic acids

out of the cell and bases,

FACILITATED Along concentration gradient, Vit B12
- DIFFUSION- movement of molecules based on the W ithout the use of energy,

differences in the concentration across 2 regions VESICULAR This is the only transport Fats, glycerin, starch, Parasite
- PINOCYTOSIS process that does not require a eggs, Vitam ins A, D, E and
- CONVECTION- molecules are transported by the - PHAGOCYTOSIS drug to be in aqeous solution K, Sabin polio vaccine

movement of a liquid or a gaseous vehicle to be adsorbed:

ION-PAIR Form ation of neutral ion pair Quaternary am m onium

com plexes with endogenous com pounds

ü Concentration gradient - the difference in the m aterials

-- Absorbed by passive
Sulfonic acids

amount of a substance inside and outside of the cell diffusion

1. Going “with the gradient”
CONVECTIVE Passing through channels in Inorganic and organic electrolytes
2. Going “against the gradient” AKA: paracellular the cell m em brane (pores) up to 150 to 400M W
3. Equilibrium exists when the concentration of molecules is the transport Ions of opposite charge of pore
same throughout a space (inside and outside the cell) lining
Ionized sulfonam ides

4
 7/12/22

Orders of Reaction
• FICK’S FIRST LAW: This law states that the rate } Order of Reaction: The way in which the concentration of drug or
reactants influences the rate of a chemical reaction or process
of diffusion of a solute molecule through a
barrier is proportional to the concentration } Zero-order Reactions
- The amount of drug A is decreasing at a constant time interval, t
gradient. } First-order Reactions
The amount of drug A is decreasing at a rate that is proportional to
dc = P (C1 – C2)
-
the amount of drug A remaining

dt } HALF-LIFE (t1/2)
- The period of time required for the amount or concentration of a drug
• FICK’S SECOND LAW: This law states that the to decrease by one half
change in concentration with respect to time - the longer the t1/2, the longer the plasma concentration to stay in the
therapeutic range
at a particular region is proportional to the
change in the concentration gradient at that } First-order half life
à t 1/2 = 0.693/k
point in the system. } Zero-order half life
à t 1/2 = 0.5Ao/ko

Compartment - Hypothetical space bound by

an unspecified membrane across which drugs are } Absorption
transferred -- Concerns the processes of entry of a drug
COMPARTMENT MODELS into the systemic circulation from the site of its
} Mamillary Model administration.
◦ Most common; One or more peripheral compartments
connected to a central compartment -- The determinants of absorption are those
◦ Central compartment: Represent plasma and HIGHLY described for drug permeation.
perfused tissues which RAPIDLY equilibrate with the drug -- Intravascular administration (e.g., IV) does not
} Catenary Model involve absorption, and there is no loss of drug.
-- Consists of compartments joined to one another -- With extravascular administration (e.g., per os
like the compartments of a train
[PO; oral], intramuscular [IM], subcutaneous [SC],
} Physiologic Pharmacokinetic Model (Flow Model)
inhalation), less than 100% of a dose may reach the
-- Considers that BLOOD FLOW is responsible for
systemic circulation because of variations in
distributing drugs to various parts of the body
bioavailability.

Intravenous Intramuscular
Routes of
Administration } Transcellular
◦ Process of drug movement across the cell

Intraarterial Intracardiac Intraarticular Intradermal } Paracellular

◦ Process of drug movement that goes through gaps or tight
junction between cell
Other Terminology:
Subcutaneous Intrathecal Intraspinal Epidural
Adsorption- Bound to the surface of the skin or mucosa
Penetration- Drug reaches the deepest layer of the
skin, yet does not reach the blood capillaries
Sorption- Penetration and permeation
Aqueous solution- Prerequisite for absorption

5
 7/12/22

Plasma concentration vs time curve } MEC (Minimum effective concentration)

◦ Needed to produce the desired pharmacologic effect
} MTC (Minimum Toxic concentration)
◦ Needed to just barely produce toxic effects
} Onset of time
◦ Time required to reach MEC
} Peak time (Tmax)
◦ time of Maximum drug conc in the plasma and a rough
marker of average rate of drug absorption
} Peak Concentration (Cmax)
◦ Maximum drug concentration
} Duration of Drug action
◦ Difference between the onset of time and time for the drug to decline
back to MEC
} AUC (Area Under the Curve)
◦ Amount of drug absorbed systematically
◦ Total area found under the plasma concentration vs time curve from
the initial dose to final elimination of the drug from the body
◦ The integral of drug level over time from zero to
infinity

} Bioavailability (f)
-- Measure of the fraction of a dose that reaches the
systemic circulation. By definition, intravascular
doses have 100% bioavailability, f = 1 } First-Pass Effect
-- With oral administration, drugs are absorbed
} Bioequivalence into the portal circulation and initially
-- For bioequivalence to occur between two
formulations of the same compound, they must distributed to the liver.
have the same bioavailability and the same rate of For some drugs, their rapid hepatic metabolism
absorption. When this occurs, the plasma levels of
the two products will be superimposable, if they are decreases bioavailability-the "first- pass" effect.
given at same dose, by the same mode.
} Cmax and tmax are rate dependent. The faster
the rate of absorption, the smaller the tmax and
the larger the Cmax, and vice versa.

↑GET, ↓GER, ↓ABS ↓GET, ↑GER, ↑ ABS

} Duodenum - has the greatest capacity

Fatty meal Cold foods
for the absorption of drugs from the GI Hot meal Mild exercise
tract Stress Motility
} a delay in the gastric emptying time for Lying on the left Lying on the
the drug to reach the duodenum will slow
side right side
the rate and possibly the extent of drug
absorption, thereby prolonging the onset Heavy exercise Standing position
time for the drugs. Anti motility

6
 7/12/22

} Distribution
} The processes of distribution of a drug from the systemic
circulation to organs and tissue involve its permeation } Central Compartment
through membrane barriers and are dependent on its solubility The central compartment includes the well-perfused
(recall that only nonionized drugs cross biomembranes), the
rate of blood flow to the tissues, and the binding of drug organs and tissues (heart, blood, liver, brain and kidney)
molecules to plasma proteins. with which drug equilibrates rapidly.
} Factors Affecting Distribution } Peripheral Compartment(s)
a. Rate of Distribution The peripheral compartments include those organs
- Membrane permeability which are less well-perfused, and with which drug
- Capillary wall structure therefore equilibrates more slowly.
- Drug’s pKa and blood pH } Special Compartments
- Blood Perfusion
These include cerebrospinal fluid (CSF) and central
b. Extent of Distribution nervous system (CNS) , the blood-brain barrier ,
- Lipid solubility pericardial fluid, bronchial secretions and fluid in the
- pH-pKa middle ear
- Tissue localization
- Plasma-protein binding

} Special Barriers to Distribution } PROTEIN BINDING

Placental: most small molecular weight drugs Albumin
cross the placental barrier, although fetal blood ◦ Major plasma protein component
levels are usually lower than maternal ◦ Reversible drug binding
Blood-brain: permeable only to lipid-soluble ◦ Acidic drugs
drugs or those of very low molecular weight Alpha-1 Acid Glycoprotein (AAG) and Globulin
◦ Basic drugs
} Plasma Protein Binding Lipoproteins
- Many drugs bind to plasma proteins, ◦ macromolecular complexes of lipids + proteins
including albumin, with an equilibrium between ◦ Binds drugs when albumin sites become saturated
bound and free molecules (recall that only RBC
• May bind both endogenous and exogenous compounds.
unbound drugs cross biomembranes).
Globulin:
- Competition between drugs for plasma may be responsible for the transport of certain endogenous
protein binding sites may increase the "free
•
substances such as corticosteroids
fraction," possibly enhancing the effects of the
drug displaced.

• Volume of distribution (VD )

• Blood flow is an important factor in
determining the initial distribution of drugs
• PERFUSION OR FLOW LIMITED
• Drug diffuse rapidly across the
membrane
• Blood flow is the rate limiting step in
distribution
• DIFFUSION OR PERMEABILITY LIMITED
• Drug distribution is limited by slow
diffusion of drugs cross the membrane
• Estimate the extent of drug distribution in
the body
• Relates the plasma conc to the amount of
drug present in the body
• theoretical volume in which the total
amount of drug would need to be uniformly
distributed to produce the desired blood
concentration of a drug

7
 7/12/22

} Depends on
CIRCULATORY SYSTEM 5L ◦ blood and tissue affinity for the drug
(reversible)
EXTRACELLULAR FLUID 10-20L
} Drugs with high tissue affinity tend
INTRACELLULAR FLUID 25-30L to accumulate or concentrate in the
WHOLE BODY FLUID 40L
tissue
} Drugs with a high lipid/water
partition coefficient tend to
accumulate in lipid tissue

Apparent Volume of Distribution (Vd)

} Drug molecules may bind to plasma
proteins
} Bound drugs are pharmacologically inactive
} free, unbound drug can act on target sites
in the tissues, elicit a biologic response,
and be available to the processes of
elimination
} A kinetic parameter of a drug that correlates dose with
plasma level at zero time.
} The higher the Vd, the lower the plasma concentration
and vice versa.
} Vd is low when a high percentage of a drug is bound to
plasma proteins. This relationship can be used for
calculating Vd by using the dose only if one knows or
can calculate C0.
} Tissue binding and accumulation of drugs with high Vd
values raise the possibility of displacement by other
agentsàchanges in pharmacologic activity

} Metabolism
Biotransformation is the metabolic conversion of
drugs, generally to less active compounds but
sometimes to isoactive or more active forms.
Drug Biotransformation Reactions
1. Active drug à polar metabolite
2. Active drug à inactive metabolite
3. Active drug à active metabolite
4. Inactive drug à active metabolite
5. Active drug à reactive metabolite
1. INACTIVE METABOLITES
Procaine → p-aminobenzoic acid
6-mercaptopurine → 6-mercaptopuric acid
amphetamine → phenylacetone (deamination)
phenobarbital → hydroxyphenobarbital
(hydroxylation)
2. METABOLITES THAT RETAIN SIMILAR ACTIVITY
Imipramine → desipramine
acetohexamide → L-hydroxyhexamide
Codeine → Morphine
Procainamide → N-acetyl procainamide(acetylation)
Phenylbutazone →oxyphenbutazone(hydroxylation)

8
 7/12/22

3. METABOLITES WITH ALTERED ACTIVITY } Phase I reactions

Iproniazid → isoniazid - Include oxidation (especially by the cytochrome P45- group
Retinoic acid → Isotretinoin of enzymes also called mixed function oxidases), reduction,
4. BIOACTIVATED METABOLITE deamination and hydrolysis
- Reactions that convert the parent drug to a more polar
Enalapril → Enalaprilat (water-soluble) or more reactive product by unmasking or
Sulindac → active sulfide inserting a polar functional group such as -OH, -SH, or -NH
Levodopa → dopamine
Prontosil → sulfanilamide } Phase II reactions
Hetacillin → ampicillin - Synthetic reactions that involve addition (conjugation) of
Sulfasalazine → sulfapyridine + aminosalicylic acid subgroups to -OH, -NH 2, and -SH functions on the drug
molecule.
5. REACTIVE METABOLITE - The subgroups that are added include glucuronate, acetate,
Acetaminophen → NAPQI glutathione, glycine, sulfate, and methyl groups.
Benzopyrene → Reactive - Most of these groups are relatively polar and make the
product less lipid-soluble than the original drug molecule.
Malathion → Malaoxon - This metabolism phase reaction is responsible for the formation
parathion→ Paraoxon of the final metabolic product of the drug to be excreted

PHASE I
A. OXIDATION +OXYGEN, - HYDROGEN
2 REQUIREMENT: NADPH AND OXYGEN

Phase 1 Reaction B. REDUCTION

C. HYDROLYSIS
+ HYDROGEN, - OXYGEN
+ WATER
ESTERASE AND AMIDASE
PHASE II MOST COMMON
1. GLUCORONIC ACID REQUIREMENT: UDPGA
CONJUGATION ENZYME: GLUCORONOSYL TRANSFERASE
2. SULFATE CONJUGATION Enzyme: SULFOTRANSFERASES OR SULFOKINASES
REQUIREMENT: PAPS
3. GLUTATHIONE DETOXIFICATION
most common MFO CONJUGATION ENZYME: GLUTATHIONE-S-TRANSFERASE
4. ACETYLATION Conjugation of aromatic primary amines, aliphatic
INDIVIDUAL GENE A. SLOW amines, amino acids, hydrazines, hydrazides and
B. FAST sulfonamides
ENZYME: N-ACETYL TRANSFERASES
SUBFAMILY Involve in drug 5. METHYLATION Enzyme: METHYL TRANSFERASE
ROOT metabolism S-adenosylmethionine is formed which reacts with the
CYP 1 drug in the presence of a methyl transferase
FAMILY CYP 2 6. Amino Acid Conjugation GLYCINE: Enzyme: COENZYME A
CYP 3 GLUTAMINE: for conjugation with organic acids such
CYP 4 as phenylacetic and related acids

Sites of Drug Metabolism

} The most important organ for drug metabolism is the
liver.
} The kidneys play an important role in the metabolism
of some drugs.
} A few drugs (eg. esters) are metabolized in many
AGE METABOLISM CAPACITY tissues (liver. blood, intestinal wall, etc) because of the
DEVELOPED broad distribution of their enzymes.
Birth Sulfation } Determinants of Biotransformation Rate
1 st week Reduction, Oxidation } Genetic factors
} Hydrolysis of esters- succinylcholine
1 month Acetylation } Acetylation of amines- isoniazid in slow and fast
acetylators
2 months Glucoronidation
} Oxidation- debrisoquin, sparteine, phenformin,
3 months Glycine conjugation dextromethorphan, metoprolol, and some tricyclic
antidepressants
Glutathione conjugation
Cysteine conjugation

9
 7/12/22

} Drug or chemical-stimulated increase in
enzyme activity
} Alteration in the enzyme activity in liver
microsomes resulting in a faster rate of
metabolism
} not a disease; it is an adaptation of the body
to exogenous material
} ↑enzymes ↑ metabolism ↓ effect
AUTO-INDUCTION
• A drug that stimulates its own metabolism
EX. Phenobarbital is given repeatedly its
metabolism is increased
FOREIGN-INDUCTION
• one enzyme inducer stimulate the rate of
metabolism of another drug
EX. If a dose of hexobarbital is then given its
metabolism is also increased

ENZYME INDUCERS } May be due to substrate competition or due

to direct inhibition of drug metabolizing
enzyme
P- Phenytoin
} ↓enzyme↓ metabolism ↑ effect
P- Phenobarbital
R- Rifampicin
C- Carbamazepine (auto-induction)
C- Cigarette smoking
C- chronic alcoholism

ENZYME INHIBITORS
M- Metronidazole
E- Erythromycin
D- Disulfiram
I- Isoniazid
I- Itraconazole
C- Cimetidine
} PRESYSTEMIC METABOLISM
C- Chloramphenicol
C- Clarithromycin } initial BIOTRANSFORMATION of an active drug
K- Ketoconazole BEFORE reaching the systemic circulation
A- Acute alcoholism } reduces the systemic availability of the drug
V- Valproic acid } IV and PO
G- Grapefruit juice (Naringin) } eg. Propranolol, NTG, Morphine, Pentazocine,
meperidine, Verapamil

10
 7/12/22

} P-glycoprotein
HT-29 -- This cultured cell model to predict
- P-glycoprotein (P-gp) has been identified as an
important modulator of intestinal drug transport and drug absorption is capable of secreting mucin,
usually functions to expel drugs from the intestinal the primary agent of the mucous barrier in the
mucosa into the lumen. intestinal mucosa.
- Drugs that inhibit intestinal P-gp mimic drug
metabolism inhibitors by increasing bioavailability and
may result in toxic plasma concentrations of drugs T-84 -- This cultured cell model is valuable in
given at normally nontoxic dosage. predicting the role of p-glycoprotein in transport
- P-gp inhibitors include verapamil, mibefradil (a drugs
calcium channel blocker no longer on the market), and
certain components of grapefruit juice.
Caco-2 -- This cultured line allows for
- Important drugs that are normally expelled by P-gp
(and which are therefore potentially more toxic when characterization of mucosal to serosal and
given with a P-gp inhibitor) include digoxin, cyclosporine, serosal to mucosal transport and can be used to
and saquinavir. study transcellular and paracellular transport

} Excretion } PATHWAYS
1. Biliary excretion
} Removal of the intact drug - Anions, cations, non-ionized
molecules with lipophilic polar groups &
} Zero-Order Elimination Rate those with MW>500
} A constant amount of drug is eliminated per unit time; for example, if 80 mg is - For drugs poorly absorbed in the
administered and 10 mg is eliminated every 4 h, the time course of drug elimination intestines
is: - Organic acids & organic bases à
active transport
- Consider biliary recycling
} Drugs with zero-order elimination include ethanol (except low blood levels),
2. Salivary Excretion
phenytoin (high therapeutic doses), and salicylates (toxic doses).
- Via different transport mechanisms
First-Order Elimination Rate
} For example, if 80 mg of a drug is administered and its elimination half-life = 4 h, 3. Mammary Excretion
the time course of its elimination is: - Nursing mothers should avoid taking
drugs
- Antithyroid, lithium, chloramphenicol,
anticancer drugs à DO NOT NURSE
- Extremely narrow therapeutic index
gentamicin, kanamycinà TAKE SPECIAL
} Most drugs follow first-order elimination rates. CARE
4. Drug Excretion Into Sweat
- Passive diffusion of the non-
ionized moiety
- Non-ionized cmpnds:
alcohol, antipyrine, urea
- Weak acids: sulfonamides,
salicylic acid
- Weak bases: thiamine
-Metals: I, Br, Hg, Pb
5. Drug Excretion Into Expired
Air
- Less soluble anesthetics
- Soluble gases
- Other volatile compounds:
alcohol, ethereal oils

6. Genital Excretion } Clearance

- Prostate secretions } Clearance is defined as the volume of blood cleared
- Seminal fluid : anticancer drugs à of the drug in unit time. It represents the
relationship between the rate of drug elimination
malformations and its plasma level.

7. Intestinal Excretion } CREATININE CLEARANCE

- Verified by the presence of drugs in the gut - Volume of blood plasma that is cleared of creatinine
lumen after IV administration by kidney filtration per minute (mL/min)
- Normal adult male range is 75-125 mL/min
- E.g. Doxycycline
COMPUTED BY:
- Cockroft & Gault
8. Renal Drug Excretion
- - JELLIFE- For adults with unstable renal
- Major route function, creatinine clearance may be computed
- Non-volatile, water-soluble, low MW drugs

11
 7/12/22

Creatinine clearance eq. B. JELLIFE EQ

A. COCKCROFT AND GAULT CrCl
CrCl 98-[(0.8)(Age in years - 20]
(140-Age)(BW in kg)
serum creatinine in mg/dL
(72)(serum conc. in mg/dL)
females = CrCl x 0.90
female = CrCl x 0.85
unit: mL/min

} filtrationof LMW molecules

1. Glomerular filtration (MW<500)
2. Active tubular secretion } normal GFR:125mL/min (180
3. Tubular reabsorption L/day)
} GFR - tells how healthy the
kidney is
} ave urine: 1-1.5 L(99% are
reabsorbed)

GFR measurement
Inulin group description Est . Creatinine
üfullills most of the criteria needed clearance
üstandard reference 1 Normal renal >80 mL/min
ü(-) time consuming function
Creatinine 2 Mild renal 50 – 80 mL/min
ü clearance of creatinine is used most extensively
as a measurement of GFR impairment
übyproduct of muscle metabolism 3 Moderate renal 30 -50 mL/min
üFemales→less muscle mass→less creatinine to impairment
excrete 4 Severe renal <30 mL/min
üElderly→declined muscle mass → lowered
production of creatinine impairment
üpx with ↓GFR→acc. serum creatinine 5 ESRD Require dialysis

12
 7/12/22

} Occurs in proximal Convuluted tubule

} Reabsorption of water and active secretion } occurs in Distal convoluted Tubule
of some weak electrolyte ( weak acids) } If a drug completely reabsorbed (eg.
} Requires carrier and energy ( against conc Glucose), then the values for the clearance
gradient) of the drug is approximately zero.
} reflects the effective renal plasma flow } For drugs that are partially reabsorbed,
clearance values will be less than the GFR
(ERPF) - 425 to 650 mL/min of 125 to 130 mL/min
Drugs used to measure active tubular secretion
P-amino hippuric acid (PAH) and iodopyracet
(Diodrast)
These substances are both filtered by the
glomeruli and secreted by the tubular cells

Reabsorption of water and passive excretion

}
of lipid soluble drugs
} Depends on urine pH
◦ Based of Henderson-Hasselbalch equation
Acidic Urine + Acidic Drug = Reabsorb
Acidic urine + Basic Drug = Excreted
Basic urine + Acidic drug = Excreted
Basic urine + Basic drug = Reabsorb
1. Renal clearance - voL of plasma
that is cleared of drug per unit time
through the KIDNEY
2. Hepatic clearance - voL of plasma that
is cleared of drug per unit time through
the LIVER
3. Creatine clearance - ratio of creatine
in the urine and creatinine in the
plasma

} Inulin and Creatinine – compounds

which are filtered through glomeruli only and
are used as a test substance for kidney
function test to determine GFR. } refers to the therapeutic effect, sub-
} Bromosulphthalein test therapeutic effect, side effect and
-- TEST used to determine liver’s capacity for toxic effect
active transport and biliary excretion.

13

NONLINEAR PHARMACOKINETICS
- Capacity-limited, dose-dependent or
saturation pharmacokinetics
- May be due to saturation of an enzyme- or
carrier-mediated system
- Does not follow first-order kinetics as the dose
is increased
} - Described by Michaelis-Menten equation,
Enzyme kinetics, Saturation kinetics
Pharmaceutical equivalents – drug
products that contains identical dosage form,
API, chemical form, dosage strength, route of
administration, intensity and duration of
action, and salt/ ester.
They may differ in characteristics such as shape,
scoring configuration, release mechanisms,
packaging, excipients (including colors,
flavors, preservatives), expiration time, and,
within certain limits, labeling
To establish bioequivalence the calculated
confidence interval should fail within the usually
prescribed limit of ___ for the ratio of the product
averages.
Therapeutic equivalents- drug products that
are pharmaceutical equivalents and can be
expected to give the same therapeutic effect
when administered to the patient under the
conditions specified in the labelling
- same active substance or therapeutic moiety
- have the same clinical effect and safety profile
when administered to patients
- SAME DOSAGE STRENGTH OF ACTIVE CHEMICAL
INGREDIENT, DOSAGE FORM, INTENSITY AND DURATION
OF ACTION
7/12/22
PARAMETERS FOR ASSESSMENT
BIOAVAILABILITY
} Peak height concentration –is the
maximum drug concentration observed in the
blood plasma or serum following a dose of the
drug (cmax)
} Time of the peak concentration – the
time required to achieve the maximum level of
drug in the blood (Tmax)
} Area under the curved – a representative
of the total amount of drug absorbed into the
circulation following the administration of a
single dose of that drug (AUC)
Biological equivalents – pharmaceutical
equivalents/ pharmaceutical alternatives which
when administered to the same individual, in the
same dosage regimen, will result in comparable
bioavailability
} -- SAME ACTIVE CHEMICAL INGREDIENT, DOSAGE
STRENGTH OF ACTIVE CHEMICAL INGREDIENT,
DOSAGE FORM, INTENSITY AND DURATION OF
ACTION, THERAPEUTIC EFFECT and
BIOAVAILABILITY
ASSESSMENT: in vivo pharmacokinetics, in vivo
pharmacodynamic studies, comparative clinical
trials AND comparative in vitro studies
Pharmaceutical alternatives – . Drug products that
contain the same therapeutic moiety but as different
salts, esters, or complexes.
-- SAME API AND ROUTE OF ADMINISTRATION
14
 7/12/22

} Usual dose – the amount that may be expected to } Prophylactic dose – the amount administered
produce, in adults, the medicinal effect for which it is
intended to a patient before exposure or contraction of the
illness
} Initial dose – also the priming or loading dose, is the } Therapeutic dose – the amount which is
amount required to attain the desired concentration of
the drug in the blood or tissues administered to a patient after the exposure or
contraction of an illness
} Pediatric dose – dose administered to children
} Usual dosage range – amounts of drug that
} Maintenance dose- dose required to maintain may be prescribed within the work of usual medical
clinical effectiveness/therapeutic concentration practice
according to dosage regimen

} BIOPHASE– Actual site of pharmacologic action of

CLASS 1 INCREASE SOLUBILITY,
INCREASE PERMEABILITY
CLASS 2 DECREASE SOLUBILITY,
INCREASE PERMEABILITY
CLASS 3 INCREASE SOLUBILITY,
DECREASE PERMEABILITY
CLASS 4 DECREASE SOLUBILITY,
DECREASE PERMEABILITY
drugs in body
} STEADY STATE- rate of drug leaving the body =
DILTIAZEM rate of drug entering the body
} Depot phase - A portion of a prolonged release
NIFEDIPINE dosage form which liberates the drug from the form at a
slower rate that is unrestricted absorption rate
} Absolute BioA- This refers to the systemic
INSULIN availability of a drug after extravascular administration
compared to IV dosing.
} BIOWAIVER- This term is applied to a regulatory
approval process in which an application is approved
TAXOL based on experience of equivalence of a generic drug
bioequivalence/in vivo equivalence testing.

} Dose dumping- It is the term used to describe

the accidental fast release of drug from a sustained ABSOLUTE BIOAVAILABILITY:
release dosage form = AUC EV X DOSE IV
} Residual Method/ Feathering-- This refers AUC IV X DOSE EV
to a graphical method for separation of exponents
such as separating the absorption rate constant
from the elimination rate constant.
RELATIVE BIOAVAILABILITY:
= AUC EV X DOSE IV
} Flip-flop Model-- This is observed upon topical
AUC IV X DOSE EV
or rectal route of administration where the
absorption is slower than the elimination.

15