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(An idea on drug distribution, metabolism and excretion with
Final year P.G scholar.
Department of R&B,
Regional blood flow
•Regional blood flow
Partition of drug b/w blood and body tissue based on.
- Transmembrane pH
- Lipid solubility
Initial distribution to well perfused organs(heart, liver,
second phase distribution to large fraction of body mass
like muscle, skin, fat etc.(greater time needed to reach
Drug absorption or systemic administration.
Diffusion to interstitial or intercellular fluid.
Plasma protein and drug
- Albumin – Majorly binds with acidic
- α1 – acid glycoprotein – binds with basic
- Non specific binding forming irreversible
covalent binding of reactive drugs
like alkylating agents.
- Specific binding – sex hormone binding
globulin for oestrogen and
The bound unbound drug
concentration is determined by
- Affinity of binding sites.
- Number of binding sites.
- Existinc Pathology eg; liver diseases,
nephrotic syndrome causes
cancer, arthritis, MI, Crohns disease elevate
α 1 –acidglycoprotein enhancing
binding of basic drugs.
Drug- drug interaction – competition or
site, alteration of physiology, etc.
Effects of protein binding.
•Limits drug concentration in tissues and site of action.
•Only the unbound drug is in equilibrium across the
•limits the drugs glomerular filtration.
•Drug transport and metabolism are also limited.
Tissue concentration of drugs
-Many drugs accumulate in the tissues at higher
concentrations than those in extra cellular fluids and blood.
-Eg. antimalarial drug quinacrine- liver concentration may
exceed several thousand times than blood concentration.
-The tissue concentration build up can be due to.
•Tissue binding( mostly reversible) to
- Nuclear proteins, etc
Effects of tissue
concentration of drugs
•local drug toxicity e.g; Gentamicin
in kidney and vestibular system.
- Trans cellular fluid
- Sites with active transport of drugs and
tissues with affinity to drugs. Vary with
the type of drug. Eg, liver, kidney, etc
Fat as reservoir
-Many lipid soluble drugs are stored in by physical
solution in neutral fat.
-A stable reservoir due to relatively low blood
Difficulty to predict lipophilic drug distribution in
Eg, β blockers, barbiturate thiopental.
•Tetracycline antibiotics and heavy metals adsorb onto bone
surface and eventually to crystal lattice.
•Reservoir for slow release toxic agents e.g. lead or radium
.Their effects persist long after their exposure has stopped.
Treatment of osteoporosis by
phosphonates like sodium etidronate
which is resistant to
pyrophosphatases enzyme thus
stabilizes bone matrix.
Transcellular fluid reservoir:
•Drugs cross the epithelial cells and accumulate in
the transcellular fluids.
•The major trans cellular reservoir being the
gastrointestinal tract and others are CSF, aqueous
humor, endolymph, synovial fluid,etc.
•The levels accumulated are not significant.
• The redistribution from site of action to other sites
cause termination of drug effect before drug withdrawal.
•Primarily seen when a highly lipid soluble drug that acts
on brain or cardiovascular system is administered rapidly
by intravenous injection or inhalation.
•As the I V administration is ceased once attaining the
peak concentration in the desired tissue, the drug
diffuses to other tissues like muscles. Gradually the
concentration in desired tissue falls to match the plasma
CNS and cerebro spinal fluid.
-Factors preventing transport of drug to brain
1. BBB (brain capillary endothelium and pericapillary
2. Blood CSF barrier (at choroid plexus where
epithelial cells are joined by tight junctions.)
Drug penetration into the brain depends on trans-
Essential factors for uptake
of drug by brain.
• Meningeal and encephalic inflammation
increases local permeability.
• Recently BBB destruction has emerged as
a strategy in treatment of certain brain
tumors where the intention is to directly
deliver the chemotherapy agent to the
brain tumor while maintaining the
cognitive function that is often damaged
by conventional radiotherapy.
Volume of Distribution:
-Relates to the amount of drug in the body to the
concentration of drug in blood /plasma depending
on the fluid volume.
The blood plasma volume of a 70kg man is
considered to be 3l
blood volume is 5.5l.
The extracellular fluid volume 12l
total body water is 42l.
The volume of drug distribution
•pKa of drug
•the degree of binding to plasma
•partition coefficient of drug in fat.
•Degree of binding to other tissue.
Age, gender, disease, body
Phase 1- functionalization
• introduce a functional
group to parent compound.
• Loss/ alteration of
• Enzyme system located
mainly in endoplasmic
Pase 2- biosynthetic reaction
• Formation of covalent
linkage between the
functional group of phase 1
glucuronic acid, sulphate,
glutathione, amino acids or
acetates. >> Actively
• Enzymes mainly located in
Systems involved in drug
•Cytochrome P450 mono oxygenase
Cytochrome P450 mono oxygenase system
-Heme containing membrane protein found in smooth
endoplasmic reticulum of numerous tissues.
-catalyzes wide range of oxidative and reductive reactions.
-the xenobiotic substrates reacts with the Fe3+ of the
cytochrome P450 and form enzyme substrate complex and
thereafter further reactions of biotransformation proceeds.
Electons from NADPH is utilized by it.
- 12 gene families have been identified for cytochrome P450
enzyme and a number of distinct cytochrome P450 exist in a
- Found in endoplasamic reticulum of human liver
intestine and other tissues.
- The alcohol and amine group exposed following
the hydrolysis of esters and amines are the
- Hallmark of phase 2.
- Most significant is glucuronidation following which
there is increased water solubility and promotes drug
elimination through urine.
- conjugation of electrophilic metabolites of
xenobiotics with tripeptides of glutathione is the
major detoxification pathway for drugs and
Factors effecting drug metabolism
-For an increasing number of enzymes allelic variants
with different catalytic activities have been identified.
-The differences involve a variety of molecular
mechanisms leading to complete lack of activities, a
reduction in catalytic ability or in case of gene
duplication enhanced activity.
The activity of most of the drug metabolizing
enzymes may be modulated by exposure to
certain exogenous compounds. These may
result in :-
•Inhibition of drug metabolism
•Inuction of drug metabolism
•Disease factors: k
- Hepatitis , alcoholic liver disease, biliary
cirrhosis, fatty liver and hepatocarcinoma can
potentially lead to impaired drug metabolism.
- The oral availability of drugs that undergo first
pass metabolism and reduced bioavailability is
increased 2-3 fold.
- Severe cardiac failure and shock can result in
both decreased perfusion of liver and impared
•Age and sex:
•Cytochrome P450 isoforms develop early in foetal
development but levels at birth are lower than those found
•Both phase 1 and phase 2 enzymes begin to mature
gradually following the first two to 4 wks. Thus newborn
infants are able to metabolize drugs but slower than adults.
•Elderly generally requires moderate reduction in drug dose
and awareness of possibility of exaggerated
•Responsiveness of men and women may be different for
certain drugs. some sex related
Excretion of drugs
Polar compounds excreted more efficiently than the lipid
Drug is excreted as
Involve 3 distinct process
Age and renal function
Neonates – low renal function low in the beginning
which matures rapidly.
In adulthood the renal function gradually declines approx
1% per year.
Elderly- substantial rate of renal impairment.
Factors determining drug entry to
•Extend of plasma binding(unbound drug
•Carrier mediated tubular secretion in PCT
•Reabsorption by membrane transport at
•Passive reabsorption non ionized forms of
wk acids and bases in PCT and DCT
•pH of urine( alterations can result in
significant change in drug elimination
•saliva- some drug concentration here
parallels plasma concentration thus can be
collected when inconvenient to collect blood.
Ethanol n urea readily enters B.M.
•breast milk- slightly more acidic than plasma
basic compounds may be accumulated
Elimination by these routes depends mainly on
diffusion of non-ionized lipid soluble form of drugs
through the epithelial cells of the gland based on pH.
Biliary and fecal excretion
•transporters present in the
canalicular membrane of
hepatocytes actively secrete drugs
and metabolites into the bile
Secretory transporters on the apical membrane
of enterocytes causes direct secretion of drugs
and metabolites to the intestinal lumen.
intestine for hepatic
It is the term used to indicate the fractional extend to which a
dose of drug reaches its site of action.
The bioavailability depends on
•Nature of drug
•Route of administration.
•Anatomical site from which absorption takes place
•Other anatomical, physiological and pathological factors.
When the hepatic Clearence of the drug is more in relation to
the hepatic circulation the bioavailability of drug when orally
administerd will be low. so is the case of other routes that is
subjected to first pass loss.
More biovailability is possibly be in the
1. Basthi prayoga.
2. Oral intake
3. Abhyandadi bahya prayoga
5. Nethra kriyakrama