Pharmacokinetics

lecture 2
pharmacokinetic
bioavailability
bioavailability is the rate and extent to which an administered drug
reaches the systemic circulation. for example, if 100 mg of a drug
is administered orally and 70 mg is absorbed unchanged, the bioavailability
is 0.7 or 70%. determining bioavailability is important for
calculating drug dosages for nonintravenous routes of administration
determination of bioavailability: bioavailability is determined
by comparing plasma levels of a drug after a particular route
of administration (for example, oral administration) with levels
achieved by iv administration. after iv administration, 100% of the
drug rapidly enters the circulation. when the drug is given orally,
only part of the administered dose appears in the plasma. by
plotting plasma concentrations of the drug versus time, the area
under the curve (auc) can be measured. the total auc reflects
the extent of absorption of the drug. bioavailability of a drug given
orally is the ratio of the auc following oral administration to the
auc following iv administration (assuming iv and oral doses are
equivalent figure 1.10).
. factors that influence bioavailability: in contrast to iv administration,
which confers 100% bioavailability, orally administered
drugs often undergo first-pass metabolism. this biotransformation,
in addition to the chemical and physical characteristics of the drug,
determines the rate and extent to which the agent reaches the
systemic circulation.
a. first-pass hepatic metabolism: when a drug is absorbed
from the gi tract, it enters the portal circulation before entering
the systemic circulation (figure 1.11). if the drug is rapidly
metabolized in the liver or gut wall during this initial
passage, the amount of unchanged drug entering the systemic
circulation is decreased. this is referred to as first-pass
metabolism. [note: first-pass metabolism by the intestine
or liver limits the efficacy of many oral medications. for
example, more than 90% of nitroglycerin is cleared during
first-pass metabolism. hence, it is primarily administered
via the sublingual or transdermal route.] drugs with high
first-pass metabolism should be given in doses sufficient to
ensure that enough active drug reaches the desired site of
action.
b. solubility of the drug: very hydropinghilic drugs are poorly
absorbed because of their inability to cross lipid-rich cell membranes.
paradoxically, drugs that are extremely lipophilic are
also poorly absorbed, because they are totally insoluble in
aqueous body fluids and, therefore, cannot gain access to the
surface of cells. for a drug to be readily absorbed, it must be
largely lipophilic, yet have some solubility in aqueous solutions.
this is one reason why many drugs are either weak acids or
weak bases.
c. chemical instability: some drugs, such as penicillin g, are
unstable in the ph of the gastric contents. others, such as
insulin, are destroyed in the gi tract by degradative enzymes.
d. nature of the drug formulation: drug absorption may be
altered by factors unrelated to the chemistry of the drug. for
example, particle size, salt form, crystal polymorphism, enteric
coatings, and the presence of excipients (such as binders and
dispersing agents) can influence the ease of dissolution and,
therefore, alter the rate of absorption
. drug distribution
drug distribution is the process by which a drug reversibly leaves the
bloodstream and enters the interstitium (extracellular fluid) and the tissues.
for drugs administered iv, absorption is not a factor, and the initial
phase (from immediately after administration through the rapid fall in
concentration) represents the distribution phase, during which the drug
rapidly leaves the circulation and enters the tissues . the
distribution of a drug from the plasma to the interstitium depends on cardiac
output and local blood flow, capillary permeability, the tissue volume,
the degree of binding of the drug to plasma and tissue proteins, and the
relative lipophilicity of the drug.
blood flow
the rate of blood flow to the tissue capillaries varies widely. for
instance, blood flow to the “vessel-rich organs” (brain, liver, and kidney)
is greater than that to the skeletal muscles. adipose tissue, skin,
and viscera have still lower rates of blood flow. variation in blood
flow partly explains the short duration of hypnosis produced by an
iv bolus of propofol . high blood flow, together with
high lipophilicity of propofol, permits rapid distribution into the cns
and produces anesthesia. a subsequent slower distribution to skeletal
muscle and adipose tissue lowers the plasma concentration so
that the drug diffuses out of the cns, down the concentration gradient,
and consciousness is regained.
capillary permeability
capillary permeability is determined by capillary structure and by
the chemical nature of the drug. capillary structure varies in terms
of the fraction of the basement membrane exposed by slit junctions
between endothelial cells. in the liver and spleen, a significant
portion of the basement membrane is exposed due to large,
discontinuous capillaries through which large plasma proteins can
pass . in the brain, the capillary structure is continuous,
and there are no slit junctions to enter
the brain, drugs must pass through the endothelial cells of the
cns capillaries or be actively transported. for example, a specific
transporter carries levodopa into the brain. by contrast, lipid-soluble
drugs readily penetrate the cns because they dissolve in the
endothelial cell membrane. ionized or polar drugs generally fail to
enter the cns because they cannot pass through the endothelial
cells that have no slit junctions . these closely juxtaposed
cells form tight junctions that constitute the blood–brain barrier.
binding of drugs to plasma proteins and tissues
1. binding to plasma proteins: reversible binding to plasma
proteins sequesters drugs in a nondiffusible form and slows
their transfer out of the vascular compartment. albumin is the
major drug-binding protein and may act as a drug reservoir (as
the concentration of free drug decreases due to elimination, the
bound drug dissociates from the protein). this maintains the freedrug
concentration as a constant fraction of the total drug in the
plasma.
2. binding to tissue proteins: many drugs accumulate in tissues,
leading to higher concentrations in tissues than in the extracellular
fluid and blood. drugs may accumulate as a result of binding
to lipids, proteins, or nucleic acids. drugs may also be actively
transported into tissues. tissue reservoirs may serve as a major
source of the drug and prolong its actions or cause local drug
toxicity. (for example, acrolein, the metabolite of cyclophosphamide,
can cause hemorrhagic cystitis because it accumulates in
the bladder.)
. lipophilicity
the chemical nature of a drug strongly influences its ability to cross
cell membranes. lipophilic drugs readily move across most biologic
membranes. these drugs dissolve in the lipid membranes and penetrate
the entire cell surface. the major factor influencing the distribution
of lipophilic drugs is blood flow to the area. in contrast, hydropinghilic
drugs do not readily penetrate cell membranes and must pass through
slit junctions.