PHARMA A 1.

2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13 2B-Medicine

PHARMACODYNAMICS Characteristics of Diffusion

- Study of how drugs affect the body 1. Unsaturable
2. Lacks competition
PHARMACOKINETICS
3. Does not require energy
- Study of how body deals with/process the drugs
- Important because it will determine the conc. of drug in the
body at any point of a given time Sources of variation in permeability of a given membrane:
- Involves 4 processes: ADME 1. Molecular size – large molecules have a hard time
o Absorption squeezing through small pores
o Distribution 2. Lipophilicity - Membranes in the body is a lipid bilayer
o Metabolism so only lipophilics can easily cross the membrane
o Excretion
3. Charge – highly charged molecules have difficulty in
*Disposition: entails only study of 3 processes only – permeating membranes
distribution, metabolism & excretion 4. Membrane thickness – thicker membranes = slower
movement
*Elimination: metabolism & excretion 5. Surface area – greater SA = faster net rate of movement
* The larger and more polar a molecule, the slower is its
movement across membrane.

Q1. When is equilibrium achieved?

Q2. What type of molecules move paracellularly?

B. CARRIER MEDIATED TRANSPORT

1. Passive Facilitated Diffusion
Characteristics:
When a drug is administered, it is absorbed into the systemic  requires transport system but without energy
circulation then blood vessels will distribute it to the site of action expenditure
where it will elicit its effect. It will then be metabolized by the liver,
 moves down concentration gradient
making it more water soluble for easy excretion by the kidneys.
 reaches equilibrium
KEY PHYSIOLOGIC PRINCIPLES IN PHARMACOKINETICS  saturable (have transport maximum/saturable
transport - transport system becomes full so it slows
TRANSPORT PROCESSES down or stops)
A. DIFFUSION  specific
- natural tendency for molecules to move down a  prone to competitive inhibition
concentration gradient (area of high to low conc.) Ex. movement of glucose into erythrocytes or vit B12
- most common way a drug is transported across gastrointestinal epithelium
- requirements: molecules has to be suspended in an
aqueous solution & it has to pass through a semi- 2. Active Transport
permeable membrane Characteristics:
- net rate of diffusion is dependent on permeability and  requires metabolic energy
surface area of the membrane & the conc. from one  net movement can be against concentration gradient
side to the other  saturable
- reaches equilibrium when the movement of molecule  specific
from one compartment to another is equal (movement  prone to competitive inhibition
never stops it just equalizes) Ex. Renal and biliary secretion of many acids and bases
Net rate of penetration = P x SA x (C side 1 – C side 2)
P = permeability of the membrane SA = surface area
C = concentration

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PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13
BLOOD FLOW
- blood vessels or capillaries in the body have different
characteristics (some have gaps and some doesn’t)
2 Types of Movement of Drug Molecules from intravascular
space to the extravascular space:
o Transcellular
- Lipid soluble drug molecules can easily pass through the
cell membrane
o Paracellular or Convective flow
- Slightly polar drugs cannot move transcellularly so they
move in between cells in capillaries with significant gaps
A. Perfusion Rate Limited Transportation
- Movement of drug wherein the only limiting factor
from intravascular space to the tissues is PERFUSION
because capillaries are perforated (MW or other
factors does not matter)
- If there is increased blood flow, there will be greater
drugs transported
- Examples are transport to capillaries in small intestines
& glomeruli
** When membranes offer no resistance to movement of
molecules, the rate limiting step is perfusion.
B. Permeability Rate Limited Transportation
- limiting factor is dependent on PERMEABILITY OF
CAPILLARY WALL
- example is the blood brain barrier wherein drugs
should be lipophilic to pass through
** As membrane resistance to molecules increases, the
rate of diffusion is limited by membrane permeability
IONIZATION
pH Partition Coefficient Hypothesis
- only unionized, non–polar drugs penetrate the membrane
- unionized = lipophilic  can travel across membranes
*pKa – the pH at which the ionized and un-ionized
concentrations are equal to 1
Henderson-Hasselbach Equation
For Acids:
 Weak acids with pKa >7.5: majority of fraction is in un-
ionized form at all pH values so transport is very rapid
independent of ph.
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2B-Medicine
 pka values bet 3 – 7.5: Fraction of un-ionized portion
changes for acids (only time when computation is necessary)
 For strong acids with pKa <2.5: fraction un-ionized is so
low that transport is also slow even in the most acidic
conditions.
For Bases:
 A weak base with pKa < 5 is mostly in un-ionized form at
all pH values and transport is independent of pH.
 pKa between 5 and 11: Fraction of un-ionized portion for
strong bases varies; hence transport is pH-dependent.
Remember: The effect of pH on the rate of penetration is
expected only if the limitation is in permeability.
Shows the effect of molecular size, lipophilicity and charge on the
diffusion of substance across membranes. (more applicable if this is
permeability rate limited)
PROTEIN BINDING
- When drug reaches the system, it binds to plasma & tissue
proteins
 Acidic drugs bind to albumin
 Basic drugs bind to α-1-glycopreotein
- Binding is usually reversible because fraction of unbound
bound should be equal
 when there is inequality, fraction bound will be
converted/released to become free so equilibrium is
again reached
 Unbound or free drugs  freely move & cross
membranes
 Bound drug  inactive (cannot be distributed &
excreted)
- Binding sites are not selective
NOTE: Protein binding and ionization can only affect the
rate of diffusion if the rate limiting step is the permeability
and NOT the perfusion.
PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13
PHARMACOKINETICS
- Describes the time course of drug concentration in the
body
- 4 processes involved: ADME
DEFINITION OF TERMS:
• Bioavailability (BA)- fraction of the dose of a drug that
ultimately reach the systemic circulation after it has been
administered
• Bioequivalence – comparison of bioavailability of two
drugs with the same active ingredients (sometimes this is
the difference between a generic and branded drug)
OVERVIEW (This is not in the lecture but it may help in grasping the whole
concept of ADME )
What happens to a tablet once you take it?
1. The tablet of course is placed in the mouth, then it will travel to
the esophagus, to the stomach (some absorption here) and finally
to the small intestines.
2. In the intestines, drug must be lipid soluble for it to be absorbed.
This is the major site of absorption of most drugs.
3. From the intestines, drug will pass through the portal circulation
& go to the liver where it will undergo first pass effect.
• First pass effect - phenomenon wherein a drug passes by the
liver undergoing metabolism before reaching the systemic
circulation ( this will decrease potency of drugs)
• Note that metabolism in the liver can be of 3 processes:
- Converting active drugs to inactive
- Converting active drugs to active metabolites
- Converting inactive drugs to active
4. After that, it will pass through the hepatic vein, to the IVC, to the
heart and finally to the systemic circulation.
5. In the circulation, drugs will meet the plasma proteins (albumin,
α-1-glycopreotein) and some will bind to it; the ones who are free
(unbound) will now be distributed to the target tissues/organ
eliciting their therapeutic/clinical effect.
6. As we know, most drugs only weakly bind to their receptors in the
target organ, so eventually they will dissociate & go back to the
systemic circulation for elimination.
- If they are water soluble or polar, they will go straight to the
kidneys for excretion
- If they are non polar, they will go first to the liver (second pass)
for metabolism making them more water soluble so now can be
excreted by the kidneys
ROUTES OF DRUG ADMINISTRATION
o Intravascular route
- Refers to drug administration directly to the blood 
Intravenously & Intra-arterially
- Has 100% bioavailability
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2B-Medicine
o Extravascular route
- Administration of drug via the following:
Oral Subcutaneous Rectal
Sublingual Dermal
Buccal Pulmonary
*To enter the blood, drugs administered extravascularly must
be absorbed. No absorption step is necessary when a drug is
administered intravascularly.
ABSORPTION
- the process by which unchanged drug proceeds from site
of administration to site of measurement within the body
- Goal: have most drugs in the circulation
A. GASTROINTESTINAL ABSORPTION (ORAL ROUTE)
Factors affecting gastrointestinal absorption:
1. pH of the drug
- Weakly acidic drugs are more rapidly absorbed in an
acidic environment and weakly basic drugs are more
rapidly absorbed in a basic environment (pH partition
coefficient hypothesis)
• pH: 6.6 - duodenum
• pH 7.5 - terminal ileum
• pH 6.4 - cecum
• pH 7 – colon
2. Surface area of the absorbing organ
- Small intestine: total absorptive area is 200M2 
longer stay  better absorption
-
Stomach: total absorptive area is 1M2
3. Permeability
- Small intestine (SI) > Stomach and colon
• SI is more permeable because absorption is
perfusion rate limited (more wide gaps in
endothelium)
- Polarity of molecules also affect permeability:
• Molecular size of lipophilic drugs does not affect
absorption because these drugs traverse the
membrane transcellularly.
• Polar drugs with high molecular weight moves
paracellularly via tight junctions and between
epithelial cells thus permeability is greatly reduced
if the molecular weight is >350g/mole.
*The permeability and surface area decrease progressively
from the duodenum to the colon.
PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13
Cont. Factors affecting gastrointestinal absorption:
4. Blood flow (for perfusion rate limited absorption)
- Rate of perfusion in SI: 1L/min
- Rate of perfusion in stomach: 150ml/min
**Note: Despite the pH partition coefficient hypothesis,
the absorption of a drug, be it weakly acidic or weakly
basic, is largely affected by the surface area, permeability
and perfusion. Thus, most drug absorption happens in the
small intestine.
5. Gastric emptying and intestinal motility
- Fats – slows gastric emptying
- The slower the gastric emptying time, the greater the
absorption because there is longer contact time
6. Dissolution
- Ability of a drug to be dissolved in the environment
- Associated with the physicochemical properties of the
drug (difference of generics and branded drugs)
Absorption of most drugs from intramuscular and
subcutaneous sites is perfusion rate limited. Increasing the
blood flow would also increase the rate of absorption.
Large polypeptide drugs (eg. GCSF), given IM, SC or
intraperitoneally, reach the systemic circulation by:
a. Diffusion through interstitial fluids and fenestrations
of the capillary wall
b. Convective flow through the lymphatic channels
where flow is slow and absorption may continue for
hours.
B. INTRAMASCULAR & SUBCUTANEOUS ROUTE
Factors affecting rate of absorption:
1. Perfusion
- IM more perfused than SC because there is more
blood vessels in muscles compared to SC tissues 
faster rate of absorption in IM than SC
2. Lymphatic transport
- Not all drugs given in IM or SC will be absorbed by the
BV, some will be absorbed by the lymphatics (e.g.
Peptide drugs)
- Lymph has larger pores so even large peptides can be
absorbed (reason why peptides are not given orally)
- In here, movement is by diffusion & convectional flow
(paracellular)
*Site of administration of same routes is also important in
determining rate of absorption of a drug
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2B-Medicine
- e.g. Insulin - usual route is SC, but deltoid admin will have
faster rate of absorption than if it is administered via the
buttocks
3. Temperature
- Temp will have greater effect to the vessels (dilation or
constriction)
- E.g. if you put warm water on site of admin, vessels will
dilate and therefore there will be greater blood flow
and more drug is delivered
4. Degree of rubbing
- rubbing will enhance circulation in the area, and thus
enhance absorption
All these factors will affect BA, with that said, route of
administration greatly affects BA of a drug.
- some drugs are not given orally because they have low oral
BA due to their chemical structure (polar) or they cannot fit
the gaps within the vasculature
CAUSES OF LOW ORAL BIOAVIALABILITY:
1. Insufficient time for absorption
2. Large molecular weight; charged molecules
3. Reaction within the GIT that competes with absorption.
 Presence of enzymes also affect the absorption of
drugs
Ex. Levodopa (drug for Parkinson’s) when taken orally
undergoes decarboxylation due to presence of COMT
(cathecol-o-methyl transferase) making it inactive. It is
has now less BA, less effective.
 Substances ingested/ taken with the drugs also affect
absorption
Ex. Tetracycline (antibiotic) taken orally with milk or any
dairy products or Ca will form complexes that cannot be
absorbed.
4. Hepatic extraction or first pass effect
 First pass metabolism/effect
- loss of drug as it passes for the first time through the
liver during the process of absorption
*liver: primary metabolizing organ of drugs
Table 1-1 Representative drugs showing low oral bioavailability due
to poor intestinal permeability
Amikacin Gentamicin
Carbenicillin Neomycin
Cefamandole Pyridostigmine
Cefazolin Streptomycin
Cefotaxime Teicloplanin
Ceftazidime Vancomycin
PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13 2B-Medicine

Table 1-2 Representative reactions within the GIT that  Perfusion rate limited: Well- perfused tissues receive
compete for drug absorption from solution drug faster than poorly- perfused tissues.
REACTION DRUG COMMENT  Permeabilty rate limited: especially true for polar drug
Complexation Tetracycline Unabsorbed insoluble diffusing across tightly knit membranes; Lipophilicity
complexes with polyvalent
+2 +3 +3 and degree of ionization affect distribution
metal ions like Ca , Al , Fe
Conjugation
Sulfoconjugation Isoproterenol Loss of activity; inactive Apparent Volume of Distribution (V)
products - Not a real volume, it is just the assumed volume that
Glucoronidation salicylamide Loss of activity; inactive
reflects the extent of drug distribution at equilibrium (it is
products
Decarboxylation Levodopa Loss of activity; usually given believed that this concentration will be the same
with dopa- decarboxylase concentration as the other compartments)
inhibitor to reduce GI - Concentration of drug in the plasma after distribution is
metabolism
complete
Hydrolysis
Acid PenG Loss of activity; inactive
product
Erythromycin Loss of acitivity; inactive
products
Digoxin Products (digitoxides) have IMPORTANT: The larger the volume of distribution the
variable acitivity
smaller remains in the plasma.
Enzymatic Aspirin Forms salicylic acid with active
anti-inflammatory activity
Forms active ampicillin FACTORS AFFECTING DRUG DISTRIBUTION
Pivampicillin Loss of activity; inactive 1. Blood flow or perfusion
Insulin products
2. Membrane permeability or capillary permeability
Oxidation Cyclosporine Loss of activity; products is
less active 3. Protein binding
Reduction Sulfasalzine Active parent drug and by- - protein bound drugs has limited movement/distribution
products because it becomes bigger
Adsorption Digitoxin Adsorption to cholestyramine
- Only free drugs are active because they are the ones that
which will not be absorbed
can easily pass through membranes and bind to their
receptors
↑ fraction of unbound/free drug = ↑ apparent
DISTRIBUTION
volume of distribution
- refers to transfer of drug from one location to another
- The degree of binding is expressed as the bound:total
within the body
concentration ratio. ( Values >0.9 = highly bound)
- starting point: systemic circulation (central compartment);
- Acidic drugs – bind to albumin; Basic drugs – bind to α1-
end point: target organs
acid glycoprotein and lipoprotein
* if you get the serum concentration of a drug given - Only highly protein bound drugs with small volume of
intravenously at time zero, monitoring its concentration, distribution are affected by changes in protein binding
you will see a rapid decline in drug concentration which is *Highly protein bound drugs are drugs in which 90%
brought about by distribution when the drug from central binds to proteins as they reach the systemic circulation
compartment is distributed to the different organs. But ex: phenytoin (anti-seizure) & warfarin (anti coagulant)
note that this is not yet processed. At the end of the rapid
distribution phase or at equilibrium phase of distribution, * Scenario:
the assumption is that concentrations in different  warfarin is more than 90% protein bound in
compartments of different organs are equal. Slow circulation & therefor is inactive = no effect
metabolism of drugs follows in the elimination phase  however, if warfarin is given to a pt with
where they are readied for excretion. nephrotic syndrome (dse wherein individual
(This is explained in Katzung in page 41 of chapter 3, see excrete proteins in urine), warfarin will have no
figure 3-2 for an illustration, di ako makakita ng diagram proteins to bind to, so it becomes active and
eh.) patient will suffer from bleeding
- Can be perfusion rate limited or permeability rate limited

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PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13 2B-Medicine

METABOLISM
- Conversion of one chemical species to another mostly
occurring in the liver
- sum of all reactions in our body that leads to
biotransformation of a drug
 Biotransformation: transformation of parent drugs to
metabolites
 Converting active drugs to inactive
 Converting active drugs to active metabolites
 Converting inactive drugs to active
- Main goal for elimination: make drugs more water soluble
for easy excretion
2 Phases:
PHASE I
- result in the loss of pharmacological activity, although
there are examples of retention or enhancement of
activity
- Reactions involved: oxidation, reduction & hydrolysis Different enzymes metabolizes different drugs that we take
in; however, there are substances (food, drinks and also
- Enzymes mostly used: cytochrome p450 (cyp450)
drugs) that affect activity of an enzyme (either induce or
- End products: inhibit) which leads to either enhanced or slowed metabolism
 Water soluble, polar drugs  not reabsorbed  of drugs.
excreted
 Lipid soluble, non polar  reabsorbed  may still be FACTORS THAT AFFECT DRUG METABOLISM:
active  needs to undergo phase II metabolism 1. Age
(conjugation) 2. Genetic polymorphism
- Not all individual have the same rate of activity of
PHASE II enzymes (some are rapid & slow metabolizers)
- lead to formation of covalent linkage between a functional - Ex: NAT (N-acetyltransferase) enzyme which
group on the parent compound with glucuronic acid, metabolizes INH (isoniazid)
sulfate, glutathione, amino acids or acetate  Cocasians: slow acetylators  slow metabolism
- conjugates are inactive thus slow excretion of INH  increased possibility
- reactions involved: Glucuronidation, sulfation of toxicity
- Enzymes involved: transferase  Asians: rapid acetylators good metabolism of INH
- End product: water soluble, polar products  excreted 3. Concomitant use of other drugs
4. Exposure to environmental pollutants and industrial
chemicals
5. Disease states
6. Enzyme induction/inhibition

*you can check more info on drug biotransformation and these

enzymes on Katzung, chapter 4

EXCRETION
- Final elimination of drug from the body’s systemic
circulation via the kidney into urine, via intestines into the
bile and - feces, via sweat, skin and milk

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PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13 2B-Medicine

FACTORS THAT AFFECT EXCRETION CLINICAL PHARMACOKINETICS

1. Age - Clinical application of kinetic principles that aims to design
2. Disease states dosage regimen for patients
3. Rate of excretion - goal is to give drug to patients within the therapeutic
4. Enterohepatic recirculation (explained below) window (effective yet safe/not toxic)
5. Ion trapping (explained below) - dosage regimen tells us how much, how often & how long
a drug should be given
ENTEROHEPATIC RECYCLING
When certain drug is absorbed from the intestine goes to the liver PRIMARY PHARMACOKINETIC PARAMETERS
and converted to metabolite is secreted to the bile then to the - the only thing that alters them are physiologic variables in
intestine where it should be excreted, however, there are certain the body
enzymes that convert drugs to lipid soluble which now is
 Clearance :reflects the drug eliminating capacity of body
reabsorbed. It then goes back to the portal circulation and the whole
 Volume of distribution: distribution of drug w/in body
cycle.
 Bioavailability(BA): extent of drug uptake into the
Example: Aspirin, given for MI, has to be stopped for a week or two systemic circulation
before an operation because it undergoes significant enterohepatic
recycling, so patient will bleed if not stopped early. *Clearance & BA: determine systemic exposure of body to
the drug & that dictates how much drug should be given
PRIMARY PHYSIOLOGIC VARIABLES
PHARAMCOKINETIC
PARAMETERS
Absorption Rate Blood flow at the site of absorption, gastric emptying
(oral),
intestinal motility (oral)
Bioavailability Gastric emptying, secretion of acid in stomach and
hydrolytic
enzymes in the bile, intestinal motility
Hepatic Clearance Hepatic blood flow, binding in the blood,
hepatocellular activity
DRUGS/CHEMICALS UNDERGOING ENTEROHEPATIC Renal Clearance Renal blood flow, binding in the blood, active
RECIRCULATION secretion,
Aspirin Salicylate active reabsorption, urin pH, urine flow, GFR
Theophylline TCAD (tricyclic antidepressants) Volume of Binding in the blood, binding in the tissues,
Anticoagulants Naphthalene Distribution partitioning in the fat,
body composition, body size
Organochlorine pesticides Carbamazepine
Dapsone Digoxin SECONDARY PHARMACOKINETIC PARAMETER:
Methamphetamine Paracetamol  Half-life (T ½)
Phencyclidine Phenothiazine - Time it takes for drug conc. to go down by 50%
Phenobarbital Phenytoin - Dependent on volume of distribution & clearance
Quinine Rifampicin - determines how often a drug should be given

PRIMARY PHARMACOKINETIC PARAMETERS

ION TRAPPING MECHANISM
A. BIOAVAILABILITY: fraction of drug that reaches the
- Remember that ionized drugs are water soluble and thus systemic circulation after it has been administered
easily excreted extravascularly
- In an alkaline urine pH, weakly acidic drugs are ionized
and trapped in the kidney tubules and further excreted. Area Under the Curve (AUC): plasma conc. of a drug at any
- In an acidic urine pH, weakly basic drugs are ionized and given point of time
trapped in the kidney tubules and further excreted

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PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13 2B-Medicine

Computation for Absolute BA of a drug HEPATIC CLEARANCE

- Includes biliary excretory clearance and hepatic metabolic
clearance

Factors Affecting Hepatic Clearance:

1. Perfusion: Changes in blood flow affect considerably the
amount of drug that would be eliminated by the liver.
Hepatic blood clearance = QH x EH
QH – hepatic blood flow
EH – Hepatic extraction ratio
 ↓ hepatic extraction ratio of drug = venous drug conc.
Computation based on Drug Absorbed & the arterial drug conc. in the organ is the same.
Amount of drug absorbed = Dose x F x S *Changes in blood flow will not affect the drug conc. within
F = bioavailability the liver, the rate of elimination or hepatic clearance.
* Clearance of drugs with low extraction ratio depends on
S = chemical form
the plasma protein binding because only the free or
Sample problem: unbound drugs can easily penetrate the membranes.
Aminophylline is the ethylenediamine salt of theophylline. Therefore hepatic clearance of these drugs is directly
The preparation is 80-85% theophylline. Given that F=100%, related to the concentration of unbound drug in plasma.
a patient who took 2 tablets of 200 mg theophylline will have  ↑ extraction ratio = readily removed upon entry to the
absorbed how many mg of the drug? liver despite its binding to plasma proteins or to blood
Amt of drug absorbed = ( S) x (F) x (dose) cells.
= (0.8) (1) (400 mg) *The amount eliminated would depend on the amount
= 324 mg presented to the liver.

2. Enzyme Acitivity: If enzyme activity is the rate limiting

B. CLEARANCE
step, clearance is low and directly proportional to activity
- volume of plasma cleared of the drug per unit time
(wether induced or inhibited by another drug or disease)
- dependent on blood perfusion
- maybe described in terms of eliminating organ e.g. renal Hepatic Extraction Ratio of Representative Drugs & Metabolites
clearance, hepatic clearance, pulmonary clearance Low ( 0.3 ) Intermediate (0.3 – High (>0.7)
0.7)
Clearance (Cl) – relates rate of elimination w/ the drug conc. Carbamazepine Aspirin Alprenolol
Rate of elimination = Cl x Concentration Diazepam Quinidine Cocaine
Naproxen Codeine Desipiramine
Rate of presentation of a drug to an organ of elimination is Nitrazepam Nifedipine Lidocaine
the product of blood flow (Q) and the concentration of the Phenobarbital Natriptyline Meperidine
drug in the blood entering the arterial side. ( Q x CA ) Phenytoin Morphine
Procainamide Nicotine
The rate at which a drug leaves on the venous side is Q x CV.
Salicylic Acid Nitroglycerine
Theophylline Pentazocine
Rate of extraction Valproic Acid Propoxyphene
- amt of drug that is trapped in the liver; dependent on the Warfarin Propranolol
blood flow Verapamil
- difference between rate of presentation & rate at which a
drug leaves on venous side FIRST PASS CONSIDERATION: A drug given orally must first
Rate of extraction = Q ( CA – CV) pass the liver via the portal system. The amount or fraction of
drug that escapes elimination by the liver is the upper limit of
ORAL BIOAVAILABILITY.
Maximum oral bioavailbility = 1- Hepatic Extraction Ratio

 Extraction ratio = zero  no drug was eliminated ↑hepatic extraction ratio = ↓oral bioavailbility
 Extraction ratio = 1  no drug escapes the organ

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PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13 2B-Medicine

Biliary Excretion 2. A very weakly basic nonpolar drug whose pKa is around 6
- Bile flow – 0.5 – 0.8ml/min or below is extensively reabsorbed at all values of urine
- pH of bile – 7.4 pH. Its renal clearance is low especially when it is bound to
Characteristics of Drugs Needed to Ensure High Biliary plasma proteins. Ex. Propoxyphene
Clearance: 3. For strong bases with pKa value approaching 12 or
1. Drug must be actively secreted greater, little or no reabsorption is expected throughout
2. It must be polar the range of urine pH because of ionization. Renal
3. Its molecular weight must excedd 250g/mole. clearance is independent of urine pH. Ex. gGanethedine
***Nonpolar and small molecules maybe rebsorbed 4. For basic nonpolar drugs with pka values between 6 and
12, the extent of reabsorption varies from negligible to
RENAL CLEARANCE almost complete depending on the urine pH.Ex.
Amphetamine
RENAL HANDLING OF DRUGS
 Filtration – affected by protein binding and molecular EFFECT OF URINE pH on the REABSORPTION OF ACIDIC
size primarily in the glomeruli DRUGS
 Secretion – primarily in the proximal tubule; affected by -For Acidic drugs, an increase in pH causes more ionization.
competition in the active transport -Acids are reabsorbed less and have larger renal clearance at
 Reabsorption – in the tubules higher urine pH.
- Active reabsorption – for vitamins, electrolytes, 1. An acid with pka of 2 or less, is completely ionized at all
glucose, amino acids urine pH and is not reabsorbed. Renal clearance is high
- Passive reabsorption – depends on state of ionization, and not affected by urine pH. Ex. Chromoglycic acid
polarity and molecular weight 2. Very weak acid with pka >8 is mostly un-ionized
throughout the range of urine pH. Renal clearance is low
Factors that Influence Renal Clearance: and insensitive to pH. Ex. Phenytoin
1. Plasma drug concentration 3. For nonpolar acids whose pka lies between 3 and 7.5, the
2. Plasm protein binding renal clearance is sensitive to pH.
- Proteins with molecular weight greater than or equal to Weak acids and bases showing pH-sensitive reabsorption
20,000 are not easily filtered are genrally flow-rate dependent.
- Albumin has MW=69,000g/mole
FORCED DIURESIS AND URINE pH CONTROL
3. Urine flow – usually affects those drugs that are
1. Forced diuresis must be made only in drugs whose major
reabsorbed (↑urine flow =↓reabsorption)
route of drug elimination is the kidney.
4. Urine pH
2. The compound must be extensively reabsorbed in the
- Acid in acid; base in base  enhanced absorption
renal tubule.
- Acid in base & vice versa  enhanced excretion
3. If reabsorption is pH sensitive, forced diuresis alone, pH
***Note: GFR = 120ml/min
control alone or combination of both maybe of value.

Factors Affecting Reabsorption of Drugs in the Kidneys: *study effects of urine pH on reabs of acidic & basic drugs!
1. Polarity; lipid solubility
2. Urine flow Clearance (Cl) = (S) (F) (Dose/t)
3. Urine pH- altered by diet, drugs and clinical state of the CPss ave
patient S - salt form or chemical form (if not given, S=1)
Extremes of urine ph – 4.5 to 7.5 F – BA
CPss ave – conc. of plasma at steady state or ave plasma conc
EFFECT OF URINE pH ON THE REABSORPTION OF BASIC EX: A 60 kg pt was given phenobarbital Gr I (65 mg/tablet) 2
DRUGS x/day. Compute for Cl if ave drug conc is 20 ug/mL. F= 90%
1. A basic drug that is polar in its un-ionized form is never Cl = (0.90) (130 mg/24 hours)
reabsorbed regardless of its degree of ionization in the 20 mg/L
urine unless it is actively transported. = 0.24 L/hour
Example: gentamycin = 0.005 L/kg/hour
= 0.008 mL/kg/min

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PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13
EFFECT OF CHANGES IN PRIMARY PHARMACOKINETIC
PARAMETERS ON SECONDARY PARAMETERS
* CANNOT BE DETERMINED UNLESS EXTENT OF CHANGES IN CL IS KNOWN
↔ - NO CHANGE
HALF LIFE
K = elimination rate constant or the proportion of drug in the body
eliminated per unit time
Half life is determined by both clearance and volume of
distribution.
PATTERNS OF ELIMINATION
1. ZERO ORDER KINETIC
3. MICHAELIS-MENTEN KINETICS
- Constant amount of drug is eliminated per unit time
- Constant rate process –cannot be increased even when
the drug conc is increased
- Half life decreases as the amount in the body decreases;
dependent on initial drug concentration
Ex. A patient was given drug Y with initial plasma drug
concentration of 0.20mmol/L. After approximately 33 sec,
0.10mmol/L is eliminated and 0.10mmol/L remained. Following
zero order elimination, this drug has elimination rate of
0.003mmol/L/sec. To reduce the remaining 0.10mmol/L to half, it
will only take another 17 seconds. This drug will be totally
eliminated at approximately 67 sec.
10
2B-Medicine
2. FIRST ORDER ELIMINATION/ FIRST ORDER KINETICS
- Drug elimination is exponential
- Linear kinetic process –↑linearly with ↑in drug conc
- A constant proportion of the drug in the body is
eliminated per unit time
- Half life is concentration independent and is a constant
value
Ex. A patient was given drug X with a half life of 7 mins. This means
that if this drug follows first order kinetic, 50% of the drug is
eliminated every 7 mins. From an initial drug concentration of 0.20
mg/ml, only 0.10mg/ml would remain after 7 mins. After another 7
mins (2nd half life), 50% of the remaining drug will be eliminated so
that the remaining amount will be 0.05mg/ml. After the third half
life, only 0.025mg/ml will remain and so on…
- Follows linear kinetics until enzymes become saturated
- Enzymes responsible for metabolism /elimination
become saturated resulting in non-proportional ↑in drug
levels
- Half-life ↑with ↑dose
- Composition of the excretory products may change
- Competitive inhibition can occur
- Dose-response curves may show unusually large
increase in response to increasing dose
30
25
concentration
20
15
10
5
0
dose
phenytoin
PHARMA A 1.2 - PHARMACOKINETICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. C.R. Ravelo – 06.09.13 2B-Medicine

DRUGS UNDERGOING MICHAELIS-MENTEN KINETICS Loading Dose

- allow rapid achievement of therapeutic serum levels
- Carbamazepine - high dose given for a slow acting drug
- Diltiazem - example: phenobarbital
- Hydralazine Loading dose = (Vd) (Cp)
- Nitroglycerin (S) (F)
- Penicillamine Example: A 15 year old, 40 kg, female was diagnosed to have
- Phenytoin seizure disorder for which phenobarbital was prescribed.
- Propranolol What is the loading dose to produce a plasma concentration
- Phenobarbital of 10 ug/mL?
- Salicylate LD = Vd x Cp = (0.7 L/kg) (40 kg) ( 10 mg/L)
- Theophylline SxF 0.9
- Verapamil = 311 mg = 325 mg
5 tablets of 65 mg/tablet
Derived Values from Secondary Pharmacokinetic
Parameters
 Steady State Concentration (I.V.)
Maintenance Dose - Administration of drug in such a way as
to maintain a steady state of drug in the body, ie, just enough
 Area under the Curve (I.V.) drug is given in each dose to replace the drug eliminated
since the preceeding dose
MD = (Cl) (CPss) (t)
 Elimination half-life (S) (F)
Example: What will be the maintenance dose of
phenobarbital to produce a steady state concentration of 10
 Elimination Rate Constant
ug/mL.
MD = (Cl) (CPss) (t)
(S) (F)
 Fraction Excreted Unchanged
= (0.09 mL/kg/min x 60 min/h)(40 kg)(10 ug/mL) (24 h)
(0.9)
= 57,600ug = 57.6 mg = 65 mg
 Average Plateau Concentration (oral)
1 tablet a day or ½ tablet 2x day

 Area under the Curve (oral) *She will give computations daw so study these formulas 

A 50-kg patient took 2 tablets of 500 mg/tablet of

paracetamol. What is the estimated plasma drug
concentration if bioavailability is 80% & Vd = 0.90 L/kg?
PDC = (Dose) x (F)
Vd
= (1000 mg) x (0.8)
(0.9 L/kg) x 50 kg
= 800/45 = 17.77 mg/L
Effective concentration = 10-20 ug/mL

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