From Pharmacological
Mechanisms to Precision
Medicine
Course BBS2032
, Pharmacokinetics and pharmacodynamic principles explained (two parts)
The human body restricts access to foreign molecules; therefore, to reach its target within the body
and have a therapeutic effect, a drug molecule must cross a number of restrictive barriers en route
to its target site. Following administration, the drug must be absorbed and then distributed, usually
via vessels of the circulatory and lymphatic systems; in addition to crossing membrane barriers, the
drug must survive metabolism (primarily hepatic) and elimination (by the kidney and liver and in the
feces). ADME, the absorption, distribution, metabolism, and elimination of drugs, are the processes
of pharmacokinetics. Understanding these processes and their interplay and employing
pharmacokinetic principles increase the probability of therapeutic success and reduce the occurrence
of adverse drug events.
Pharmacokinetics is the study of processes that control how drugs reach their site of action and how
drugs are removed from the body. The goal of pharmacokinetic is find a dose regimen ensuring tissue
will exposed to a appropriate concentrations for a sufficient length of time.
,Why study pharmacokinetics?
- Important for drugs with a narrow margin between the therapeutic and toxic concentration.
- Inter-individual drug response is usually caused by difference in PK handling.
First part; Pharmacokinetics
Drug molecules move around the body in two ways:
- Bulk flow (i.e. in the bloodstream, lymphatics or cerebrospinal fluid)
- Diffusion (i.e. molecule by molecule, over short distances)
The chemical nature of a drug makes no difference to its transfer by bulk flow. The cardiovascular
system provides a rapid long-distance distribution system. In contrast, diffusional characteristics
differ markedly between different drugs. In particular, ability to cross hydrophobic diffusion barriers
is strongly influenced by lipid solubility.
Drugs needs to be:
- Be liberated; dissolved
- Absorbed; RNA vaccines for example are nota absorbed as they are way to large to pass
membranes, small molecules are very well absorbed.
- Distributed; Molecules that are able to be absorbed into the blood usually also distribute to
the adipose-tissue, brain, bone, body water, skeletal tissue. Therefore body composition is
an important factor to consider.
- Metabolised; turning the drug into a different compound and thereby also decreasing the
concentration of the drug compound, the liver can make compounds toxic.
- Excreted: Remove the drug in unchanged from the body; lungs, skins and urine.
The absorption, distribution, metabolism, and excretion of a drug involve its passage across
numerous cell membranes. Mechanisms by which drugs cross membranes and the physicochemical
properties of molecules and membranes that influence this transfer are critical to understanding the
disposition of drugs in the human body. Although physical barriers to drug movement may be a
single layer of cells (e.g., intestinal epithelium) or several layers of cells and associated extracellular
protein (e.g., skin), the plasma membrane is the basic barrier.
1. Absorption
There are four main ways by which small molecules cross cell membrane:
- By diffusing directly through the lipid;
o Passive diffusion dominates transmembrane movement of most drugs. In passive
transport, the drug molecule usually penetrates by diffusion along a concentration
gradient by virtue of its solubility in the lipid bilayer. Such transfer is directly
proportional to:
▪ The magnitude of the concentration gradient across the membrane
▪ To the lipid: water partition coefficient of the drug
▪ To the membrane surface area exposed to the drug.
o Non-polar molecules (in which electrons are uniformly distributed) dissolve freely in
membrane lipids, and consequently diffuse readily across cell membranes. The
number of molecules crossing the membrane per unit area in unit time is determined
by the permeability coefficient , P , and the concentration difference across the
membrane. Permeant molecules must be present within the membrane in sufficient
, numbers and must be mobile within the membrane if rapid permeation is to occur.
Thus, two physicochemical factors contribute to P , namely solubility in the
membrane (which can be expressed as a partition coefficient for the substance
distributed between the membrane phase and the aqueous environment)
and diffusivity , which is a measure of the mobility of molecules within the lipid and is
expressed as a diffusion coefficient. The diffusion coefficient varies only modestly
between conventional drugs, as noted above, so the most important determinant of
membrane permeability for conventional low molecular-weight drugs is the partition
coefficient. Many pharmacokinetic characteristics of a drug – such as rate of
absorption from the gut, penetration into different tissues and the extent of renal
elimination – can be predicted from knowledge of its lipid solubility.
- by combination with a solute carrier (SLC) or other membrane transporter;
- by diffusing through aqueous pores formed by special membrane glycoproteins
( aquaporins ) that traverse the lipid;
o Diffusion through aquaporins is probably important in the transfer of gases such as
carbon dioxide, but the pores are too small in diameter (about 0.4 nm) to allow most
drug molecules (which usually exceed 1 nm in diameter) to pass through.
Consequently, drug distribution is not notably abnormal in patients with genetic
diseases affecting aquaporins.
- by pinocytosis
o Pinocytosis involves invagination of part of the cell membrane and the trapping
within the cell of a small vesicle containing extracellular constituents. The vesicle
contents can then be released within the cell, or extruded from its other side. This
mechanism is important for the transport of some macromolecules (e.g. insulin ,
which crosses the blood–brain barrier by this process), but not for small molecules.
