Lecture Outline

Pharmacokinetics: Fate of drugs in the body

Dr. Thaw Zin
MBBS, MMedSc, FACTM, PhD (NSW)
Clinical Associate Professor/FMHS, UTAR

Learning Objectives
At the end of the presentation, the student is expected to understand:
The basic principle underlying pharmacokinetics
The concept of compartments and drug transport across membranes between
compartments
The fate of drugs in the body; the ADME system
The drug absorption, bioavailability and factors controlling drug absorption
The drug distribution and effect of plasma protein binding on drug action
The termination of drug activity, biotransformation and excretion

Basic Principle underlying Pharmacokinetics

Pharmacological principles states that effective drug therapy
requires appropriate drugs to be given in adequate doses for
adequate period.
Right drug, right dose & right duration
Clinical Pharmacology states that adequate concentration
(required) of the drug must reach the site of action (blood) to be
able to produce a response (desired)
2 fundemental processes which determines the concentration of
drug at any moment & any region of the body are:
Translocation of drug molecules
Chemical transformation

Concept of Compartments
Hypothetically, body can be divided into different compartments
separated by semi-permeable membranes across which drug is
transported to reach the site of action.
After bringing about its effect, drug needs to be eliminated by
metabolic inactivation, &/or by excretion from the body
Translocation (movement) of drug molecules in the body include:
Bulk flow (blood stream/central compartment)
Diffusion across membranes

Movement of Drugs across Cell Membranes

Different mechanisms by which the drugs are transported include:
Passive diffusion (lipid diffusion& aqueous diffusion)
 Filtration (glomerulus)
Specialized transport: special carrier; active transport, facilitated diffusion
Exocytois/ Endocytosis

Passive diffusion process:

Most important mechanism for majority of drugs (non-polar lipid-soluble molecules diffuses
across lipid membrane. in direction of its concentration gradient) rate depending on lipid: water
partition coefficient of drug
Biological membranes behave as simple lipid barriers for drug transfer:
Most drugs are either weak acids or weak base & tend to ionize (i.e. gain or lost electrical
charge-bearing protons, depending on pH)
The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed
by
Henderson-Hasselbalch equation:
Acids: pH = pka + log[A-]/[HA]
Base: pH = pka + log [B]/[BH+]

General: pH = pka + log [Basic form]/[Acidic form]

pKa is the pH at which 50% of the drug is ionized. It is the negative log dissociation (ionization)
constant of the drug “ka”

Movement of Drugs across Cells Membranes

Weak acids:
Absorbed both from stomach & intestine
Largely present in ionized form at blood pH
Unlikely to enter into the brain
Weak base:
Negligible absorption from stomach, mainly from intestines
Largely present in unionized form at blood pH
Likely to enter into the brain
Likely to be secreted in the stomach and saliva

Carrier mediated transport: no energy required (electro-chememical gradient)

Blood brain barrier
Gastro-intestinal tract
Renal tubule
Biliary tract
Placenta
Active Transport (pump): requires expenditure of energy.
Moves drugs such as cardiac glycosides, riboflavin against concentration gradient
Inhibited by metabolic poisons.
Nonspecific active transport of drugs, metabolites & some endogenous products occurs in renal
tubules & sinusoids which have separate mechanism for organic acids or organic bases.
 Certain drugs have been found to be actively transported in the brain & choroid plexus.
Drug Disposition
(L)ADME System
Change of drug concentration in the body, which occur with time, are related to the course of the
pharmacological effects.
A. LIBERATION:
Active ingredient of any dosage form (except IV injection, oral elixir, rectal enema, eye drops)
has to be released to form a true solution to be absorbed (disintegration).
B. ABSORPTION:
Process by which drug molecule is taken up into systemic circulation (blood stream).
Occur when drug is administered extravasculary (orally, IM, SC, rectal, topically).
When drug is given IV (IA, IC) no absorption take place because the drug is directly introduced
into the blood stream.
Small intestine - principal site of absorption from GIT (enormous surface due to villi) 75% of
drug, orally, is absorbed in 1 – 3 hours.
Stomach is not a major site of absorbing drugs, even for acidic drugs. The colon is capable of
absorbing sustained release formulation.
Factors affecting GI absorption are:
Physical state of drug
Rate of disintegration and dissolution
GI motility and gastric emptying
Surface area of absorption
Splanchnic blood flow
Destruction by gastric acid
Presence of food
Binding of drugs to food constituents or to other drugs

Absorption from Gastro-Intestinal Tract:

Rate of absorption – depends on:
Dose – first order, rate proportionate to dose/concentration at site of absorption. Not
zero order – constant
Route of administration – IV>IM>oral, gastric emptying, food.
Extent of absorption – depend on:
Route of administration (IV = 100%)
Oral – <100%, determined by:
Nature of drug & formulation, liquid are better absorbed.
Degree of ionization – pH of medium & pKa of drug
Presence of impediments – food, disease (ulcerative coltis)
Hepatic first-pass extraction
Rate of disintegration can be affected by:
Tablet/capsules which contains material-diluents, stabilizing agents, binders, lubricants, as well
as force used in compressing the tablets
Rate of dissolution is governed by:
Inherent solubility, particle size, crystal form & other physical proper-ties of drugs, reduction in
particle size increases rate of absorption of poorly soluble & slowly absorbed drugs (e.g. aspirin,
griseofulvin, spironolactone) but not for freely water soluble drug like paracetamol.
Rapid dissolution rate with fast release particles in capsule or tablet can produce rapid
absorption.
Slow release particles (e.g., modified release formulation of nifedipine) produce sustained
absorption.
Increase blood flow enhance absorption (e.g. massaging).

Bioavailability
Fraction of unchanged drug reaching systemic circulation following drug administration by any
route (designated as “F”), measured as area under blood concentration-time curve (AUC) .
Bioavailability of drug injected IV is 100%.
Bioavailability for drugs adminis-tered orally may be <100% for two main reasons incomplete
extent absorption & first-pass elimination in intestinal wall or liver or to be excreted in bile.
Incomplete bioavailability after subcutaneous or intramuscular injection is less common, but
may occur due to local binding of the drug

Rate of Drug Absorption

First- order kinetics (Exponential kinetics)
Most processes of drug absorption, distribution, & elimination can be described by first-order
kinetics (where rate of absorption & elimination is directly proportional to concentration of
drug).
Absorption/elimination rate constant (ka & ke) denotes fraction of drugs absorbed or eliminated
in unit time.
Zero-order kinetics (Saturation kinetics)
Rate of absorption or elimination remains constant irrespective of drug concentration (constant
amount of drug is absorbed or eliminated in unit time)
Seen with depot IM formulations, time release oral preparations, drug implants such as
antipsychotics and sex hormones.
Zero order elimination kinetics is seen with metabolism of alcohol, phenytoin & aspirin)

Drug Disposition
First- pass Metabolism
After absorption from gut, drug is delivered via portal circulation into liver where enzyme
systems cause biotransformation. Other tissues (GIT, kidneys, lungs) also has some metabolic
activity.
Despite good GI absorption, some drugs appear in low concentration in systemic circulation due
to significant portion of dose being metabolically inactivated in either intestinal epithelium or
liver before the drug reaches the systemic circulation.
First-pass metabolism significantly limits oral availability of highly metabolized drugs.
 Extraction Ratio (ER) = Clearance (liver)/Hepatic blood flow (Q)
Significant first pass effect or pre-systemic elimination is seen in:
Analgesics: aspirin, morphine, paracetamol, pentazocine, pethidine.
Cardiovascular drugs: glyceryltrinnitrate, isosorbide dinitrate, isoprenaline, labetalol, lidocaine,
propranolol, metoprolol, verapamil, nifedipine, prazosin.
Drugs action on CNS: chlorpromazine, imipramine, levodopa, nortriptyline.
Respiratory drugs: salbutamol, terbutaline.
Oral contraceptives.

Distribution
Entire process of transfer of drug from bloodstream to other compartments is called distribution. From
blood, drug distributes into interstitial & intracellular fluids & its distribution into other compartments is
influenced by:
Regional blood flow: Initially, well-perfused organs (like liver, kidney, brain) receive most of the
drugs, while delivery to others (like muscle, viscera, skin, fat) is much slower.
Lipid solubility of drugs: lipid insoluble drugs that permeate membranes poorly are restricted in
their distribution.
Storage in fat: occurs with substances of high lipid solubility (e.g., thiopental).
Natural barriers: Blood brain barrier & reproductive organs
Protein binding: cannot be distributed & cannot be metabolized (site of temporary loss) only free
drugs pass quickly out of capillary endothelium into interstitium.
Tissue binding affinity: some drugs have high affinity for a particular tissue & may accumulate in
those tissues (chloroquine in liver; calcium in bone – site of loss). Difficult to get rid of drug from
the body when toxic
Some diseases: like CHF, uraemia, cirrhosis, etc., can alter distribution due to changes in blood
flow, body water, permeability, binding proteins, accumulation of metabolites.

Volume of Distribution
Depending on tissue binding affinity, some drugs may accumulate in certain tissues reaching higher
concentration than in blood.
Presuming that body behaves as a single homogenous compartment with volume (V) into which drug
gets immediately & uniformly distributed:
V = Dose administerer (IV)/Plasma concentration
V = volume that would accommodate all the drug in the body, if concentration throughout the body was
same as plasma. Not real volume & has no relation to any physiological space or to body fluid volume.
V = Total amount of drung in the body (DosexF)/Concentration of drug in plasma (C)

Redistribution
Highly lipid soluble drugs given IV or by inhalation initially get distributed to organs with high
blood flow, (e.g., brain, heart, kidney, etc.)
Later less vascular but more bulky tissues (muscle, fat) take up the drug & as plasma
concentration falls, the drug is withdrawn from these sites.
 If site of action of the drug was in one of the highly perfuse organs, redistribution result in
termination of drug action. Greater the lipid solubility of the drug, faster is its distribution.
Anesthetic action of thiopentone is terminated in few minutes due to redistribution.
However, when the same drug is given repeatedly or continuous over long periods, the low
perfusion high capacity sites get progressively filled up & the drug becomes longer acting.

Plasma Protein Binding

Many drugs have affinity for plasma proteins particularly:
Albumin for acidic drugs (warfarin, NSAIDs, sulphonamides),
Lipoprotines & α1 acid glycoprotein for basic drugs (chloroquine, quinine, quinidine, CPZ
& impramine).
Drugs may bind to proteins that function as specific hormone carrier proteins such as:
Binding of estrogen or testosterone to sex hormones,
Binding of globulin or binding of thyroxin-binding globulin.
Binding is usually reversible; covalent binding of reactive drugs such as alkylating agents occurs
occasionally.
Extent of binding depends on individual compound & does not depend on pharmacological or
chemical class.
Protein binding is saturable process, depends on amount of plasma protein available.

Protein binding, however, influences drug action in following ways:

Duration of action:
Highly protein bound drugs are largely restricted to vascular compartment & tends to have lower
Vd. Serve as site of temporary storage of drugs.
Protein binding is weak & as concentration of free drug falls, bound drug is quickly released into
free form.
Free form is pharmacologically active, diffusible, available for metabolism & excretion, bound
form is inactive, not available for metabolism/ excretion.
If sufficient concentration remains in plasma and duration of action may prolong (e.g.,
sulphamethoxazole).
Magnitude of drug action:
Free form being pharmacologically active, magnitude of drug action depends on the free drug
present in the plasma.
Free form available is less with highly plasma protein bound drugs which may decrease the
magnitude of action
Erratic drug action
Saturation of binding sites - larger amount of subsequent doses remaining in plasma as free
form, leads to toxicity, even with therapeutic doses.
Drugs with larger binding capacity - may displace first drug, increasing blood levels of first drug –
toxicity. Reduced level of the second drug will give rise to decreased effect. Clinically important
drug displacement interaction are:
Salicylates displace tolbutamide; salicylates displace metotrexate; indomethacin
displace warfarin
 Sulfonamides & Vitamin K displace bilirubin (kernicterus in neonates.
However, two highly bound drugs do not necessarily displace each other if their binding sites do
not overlap (e.g. acidic drug do not generally displace basic drug and vice versa).
Unusual albumin or dysproteinaemias - may give rise to abnormal binding. e.g.,
hypoalbuminaemia in nephrotic syndrome and liver diseases.
Conditions resulting in the acute phase reaction response - (cancer, arthritis, myocardial
infarction, Crohn’s diseases) lead to elevated levels of alpha1-acid glycoprotein (acute phase
protein) and enhance binding of basic drugs.
Highly protein bound drugs
Not readily removed by hemodialysis & may need special techniques for treatment in case of
poisoning.

Tissue Binding
Tissue binding of drugs usually occurs with cellular constituents such as proteins, phospholipids,
or nuclear proteins & generally is reversible.
Due to tissue binding, many drugs accumulate in tissues at higher concentrations than those in
the extracellular fluid and blood.
Consequences:
It may serve as a reservoir that prolongs drug action, (e.g., chloroquine in liver).
It can also be several thousand folds higher than that in blood, (e.g., barbiturate thiopental in
fat).
It may exert local toxicity due to high concentration (e.g. tetracycline and heavy metals in bone).

TERMINATION OF DRUG ACTIVITY

Occurs in 4 ways:
Biotransformation (inactivation or metabolism)
Excretion
Uptake into storage sites
Redistribution (adipose tissues & entero-hepatic circulation)

Biotransformation
Defined as enzyme-catalyzed alteration of drugs by living organism.
Metabolites are usually more polar, (i.e. more water soluble), & can thus be more easily excreted
by the kidney. Most hydrophilic drugs, (e.g., streptomycin, neostigmine) are not metabolized &
are excreted unchanged.
Metabolism occurs primarily in the liver & the kidney, also in the intestines, lungs & plasma. The
cytochrome p450 enzyme family is the major catalyst of drug biotransformation reactions.
Three main CYP gene families, (i.e., CYP1, CYP2 & CYP3), are involved in drug metabolism in
human liver.
Subfamilies are designated by A, B, C. Isoenzymes CYP3A4 is responsible for metabolism of more
than 50% of the drugs.
CYP2D6 is the next most CYP isoform which metabolized nearly 20% of the drugs
Transformed products of biotransformation:
An active drug into an inactive metabolite (most drugs).
An active drug into an active metabolite (e.g., diazepam à oxazepam)
An inactive (pro-drug) into an active metabolites (e.g., cyclophosphamide [inactive anticancer
drug] à 4-hydroxy cyclophosphamide [active])
An active or inactive drug into a toxic metabolite (e.g., phenacetin à 2 –hydroxy phenacetin)

Factors modifying drug metabolism: à drug interactions

Genetic: immaturity of drug metabolizing enzyme system (newborn, especially premature),
elderly, diseases, & drug-drug interaction, hepatic blood flow, etc.
Microsomal enzyme inhibition: some drug (e.g. cimetidine) inhibit activity of drug metabolizing
enzymes & potentiate other drugs (e.g. warfarin) by decreasing their clearance. Occurs when co-
administered drugs have affinity for same isozyme as different dugs can be substrates for
different CYP450 isoenzymes.
Microsomal enzyme induction: drugs, insecticides & carcinogens can increase synthesis of
microsomal enzyme esp. cytochrome p450 and glucuronyl transferase. Induction takes 4-14 days
to reach its peak & is maintained till inducing agent is being given, thereafter enzyme return to
original state over 1-3 weeks (e.g., phenobarbitone, rifampicin).
CYP450 enzymes function as catalysts to facilitate the processes by which drugs are
transformed from its initial chemical structure to biochemical forms that have action in the
body.
Each of CYP450 subtypes (called isoforms or isoenzymes), also metabolizes certain drugs or
groups of drugs.

Excretion
Where does excretion of drugs occur?
Bile
Urine
Exhaled air
Sweat
Saliva
Systemically absorbed drugs & their metabolites are excreted from the body through kidneys into urine
& through liver into bile & consequently into feces. Other pathways include skin (sweat), lungs (expired
air), mammary glands (milk), & saliva.
Renal Excretion
Excretion of drugs & metabolites in urine involves 3 processes:
glomerular filtration,
active tubular secretion, &
passive tobular reabsorption.
Changes in overall renal function generally affect all 3 processes. Renal blood flow & glomerular
filtration rate declines after age of 50 & is low in renal failure.
 Renal function is measured by creatinine clearance, & is used for dosage adjustment of drugs
mainly excreted by kidney.
Glomerular filtration (GF):
Depends on plasma protein binding, mol wt & renal blood flow.
Free drug is cleared up to 20% while protein bound drug remain
Drug molecules with mol wt > 50,000 are excluded from GF.
Active tubular secretion:
80% of delivered drugs pass thro’ proximal tubules which actively transfer strongly charged
molecules from plasma to the tubular fluid. Two independent & relatively non-selective carrier-
mediated active transport systems are involved:
Organic acid transport: penicillin, furosemide, probenecid, salicylic/A, sulfinpyrazone,
nitrofurantoin, metrotrexate etc.
Organic base transport: thiazide, quinine, procainamide, cimetidine, amiloride,
amphetamine, etc.
Passive tubular reabsorption:
Occurs only with unionized, lipid soluble drugs, extent of drug returning by passive diffusion
into blood & depends upon its lipid solubility, on its pKa & on pH of tubular fluid.
In acid urine basic drugs are more ionized & excretion is good while in alkaline urine, mostly
remains un-ionised, hence better reabsorbed & excretion is poor. Reverse is true for acidic drugs,
vice versa.
Rate of excretion of highly ionized drugs like aminoglycosides & quarternary ammonium
compounds parallels to the GFR.
Manipulation of urinary pH is of practical importance in cases of drug poisoning (e.g., sodium
bicarbonate is often given to treat salicylate & barbiturate overdose).

Biliary Excretion
Biliary excretion is important for drugs metabolized in the liver which actively transports drugs
into bile organic acids, organic bases and steroid.
Various hydrophilic drug conjugates (particularly glucuronides) are concentrated in bile and
delivered to the intestine where glucuronide is usually hydrolyzed (deconjugated) by bacteria,
releasing active drug once more.
Free drug is then reabsorbed & the cycle is repeated, which is known as the “enterohepatic
circulation”
This effect prolongs the drug action & its half-life ( e.g., morphine, ethinyloestradiol (oral
contraceptives), ampicillin, rifampicin, tetracycline, phenolphthalein).
Finally, ultimate excretion of these occurs in the urine

Uptake into Storage Sites

Sympathetic nerves take up amines from the circulation after release. Two mechanisms are involved:
Uptake 1 –
Neuronal, has high affinity for norepinephrine & low affinity for epinephirine.
Take up catecholamine into nerve terminals. Drugs such as cocine & imipramine selectively block
this process.
Uptake 2 –
Extreneuronal, has low affinity for norepinephrine & higher affinity for epinephrine.
This transport system is present in glial, hepatic, cardic & other cells. It is not inhibited by cocine
& impramine.

Conclusion
Pharmacokinetics serve to devise:
Rational Dosage Regimen for Therapeutics, & to
Modify them according to individual needs (i.e. Individualization of Dose Regimens &
Therapeutic Drug Monitoring)
This is done through elementary pharmacokinetics utilizing fundamental pharmacokinetic
parameters; viz.
Bioavailability (F),
Volume of distribution (V),
Clearance (CL) &
Plasma half life (t ½)
Maximum plasma conc (C max)

Assignment – 2: Basic Concept & Pharmacokinetics

What is the role of pharmacology in promoting the rational use of drugs in modern day practice?
Which is the best route for drug administration in everyday use of drugs?
Elaborate the problems that physicians encounter in modern drug therapy.
What is the basic principle underlying the study of pharmacokinetics?
Why is bioavailability important & what are the factors influencing it?
Where can drug molecules bind in the body & how does it prolong the action of drugs?