22 Principles of Pharmacology - Principles of Pharmacokinetics
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Course
Pharmacology
Institution
Pharmacology
The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Prof. Carol Walsh
HST-151 1
PRINCIPLES OF PHARMACOKINETICS
Learning Objectives:
1. Describe the physicochemical and physiological factors that influence the
absorption of drugs from enteral and parenteral routes of administration, their
distribution within the body, and their routes and mechanisms of elimination.
2. Explain how dose, bioavailability, rate of absorption, apparent volume of
distribution, total clearance, and elimination half-life affect the plasma
concentrations of a drug after administration of a single dose.
3. Describe the factors which determine the time-course of systemic accumulation of
a drug administered by infusion or multiple doses.
I. Absorption of Drugs
A. Transport Across Cell Membranes
1. Passive diffusion
a. Passage through lipid cell membrane by dissolution in membrane; rate
dependent on concentration gradient and lipid:water partition coefficient of drug;
rate markedly higher for unionized form of weak electrolyte because of its higher
lipophilicity than the ionized form; obeys first-order kinetics (rate of transport is
proportional to concentration gradient at transport site).
b. Filtration through aqueous channels within membranes and between cells.
2. Active transport
a. Passage facilitated by an energy-dependent membrane carrier mechanism
such that transport can occur against a concentration gradient; transporters
include the family of ATP-dependent proteins, such as
• the multidrug resistance p-glycoprotein (amphipathic cationic and
neutral substrates, 170 kD, mdr gene product, verapamil sensitive)
• the multidrug resistance-associated proteins (MRP1-6, organic anion
substrates, 190 kD, probenecid sensitive).
b. Exhibits structural selectivity, saturability, competition between structural
analogues and genetic variants.
,HST-151 2
c. Sites for drugs in intestinal mucosa (cell to lumen), capillary endothelium
of brain and testis (cell to blood), choroid plexus (CSF to blood), proximal renal
tubular cell (blood to urine), hepatocyte (blood to bile), tumor cells (efflux pump).
d. Obeys Michaelis-Menten kinetics: if drug concentration is high enough to
saturate carrier mechanism, kinetics are zero-order (rate of transport is constant).
3. Endocytosis
a. Passage into cell within membrane invagination.
b. Important mechanism for particulates and high molecule weight
compounds, such as proteins.
B. Routes of Drug Administration
1. General determinants of absorption rate
a. Dissolution into aqueous fluids at absorption site, lipid solubility,
concentration gradient, blood flow at absorption site, surface area of absorption
site.
b. Importance of rate-limiting process
2. Oral (p.o.) Ingestion
a. Convenient route for administration of solid as well as liquid formulations.
b. Additional variables which may influence rate and extent of absorption
include disintegration and dissolution of solids, acidity of gastric contents, gastric
emptying rate, intraluminal and mucosal biotransformation by host or bacterial
enzymes, dietary contents, and presence of other drugs.
c. First-pass effect: absorbed drug passes via portal circulation through liver
which may clear substantial fraction and thus decrease bioavailability (percent of
dose which reaches the systemic circulation).
3. Parenteral Injection
a. Subcutaneous (s.c.) and intramuscular (i.m.) administration: more
extensive absorption of high molecular weight, polar molecules than by oral
route, via lymphatic circulation; absorption rate can be manipulated by
formulation, e.g. rapid from aqueous solution, slow from suspension or solid
pellet.
, HST-151 3
b. Intravenous (i.v.) injection: complete bioavailability; drugs only given in
sterile solution; important when immediate effect required; increased risk of
toxicity.
4. Pulmonary Inhalation
a. Rapid absorption of drugs in gaseous, vaporized or aerosol form.
b. Absorption of particulates/aerosols depends on particle/droplet size which
influences depth of entry in pulmonary tree; 1-5 uM particles reach alveolus
5. Topical Application
a. Usually for local effect; patch formulations for systemic effect
b. Absorption through mucous membrane may be rapid
c. Absorption through skin generally slow; enhanced by increased
lipophilicity, by damage to stratum corneum, and by increased blood flow.
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