16 MEDICINAL CHEMISTRY
Table 1.3 Percentage Protein Binding for Common Drugs
99% 95–99% 90–95% 50–90% <50%
Levothyroxine Amitriptyline Diazoxide Aspirin Alcohol
Phenylbutazone Chlorpromazine Disopyramide Carbamazepine Aminoglycosides
Triiodothyronine Clofibrate Phenytoin Chloramphenicol Digoxin
Warfarin Diazepam Propranolol Chloroquine Paracetamol
Furosemide Tolbutamide Lidocaine Procainamide
Gold salts Valproate Quinidine
Heparin Simvastatin
Imipramine Sulfonamides
(Adapted from D. G. Grahame-Smith, J. K. Aronson (2002). Clinical Pharmacology and Drug Therapy,
3rd Edn. New York: Oxford University Press. With permission.)
any possible receptor site. Due to the anatomical arrangement of blood vessels in the
abdomen, all orally administered drugs must immediately pass through the liver follow-
ing absorption from the small intestine. Accordingly, a drug molecule that is susceptible
to a first pass effect should in theory be designed and formulated in a manner that mini-
mizes small intestine absorption. One method of reducing a first pass effect is to admin-
ister the drug sublingually so that it is absorbed under the tongue and has an opportunity
of avoiding the initial pass through the liver. See figure 1.3 for anatomical details of the
three phases that a drug must endure in traveling to its site of action.
Like the liver, the kidney is another organ system that may influence the effectiveness
of a drug molecule during the pharmacokinetic phase. Small, hydrophilic, and highly
polar molecules (e.g., sulphonates, phosphonates) run a significant chance of being
rapidly excreted via the renal system. Such molecules have short half-lives (the period of
time during which one-half of the drug molecules is excreted). A short half-life reduces
the effectiveness of a drug molecule because it shortens the time duration available to the
drug for distribution and binding to its receptor. In addition, as a general rule, a drug is
administered at least once every half-life; a drug with a half-life of 24 hours may be
administered once per day whereas a drug with a 12 h half-life must be given at least twice
per day. If a drug has a half-life of 20 minutes it would be impractical to administer it three
times per hour. Table 1.4 presents the half-lives for a variety of drug molecules.
The final impediment to drug molecule effectiveness during the pharmacokinetic
phase is the existence of barriers. In order to reach its target organ, the drug molecule
must traverse a variety of membranes and barriers. This is particularly true if the drug
is destined to enter the brain, which is guarded by the blood–brain barrier. This is a lipid
barrier composed of endothelial tight junctions and astrocytic processes. The blood–
brain barrier can be exploited for purposes of drug design. Molecules can be designed
not to cross this barrier. This design feature is highly desirable if one wishes to develop
drug molecules for non-neurologic indications that will have no neurologic side effects.
On the other hand, the existence of the blood–brain barrier must be explicitly consid-
ered when designing drugs for neurological indications. Another highly relevant barrier
is the maternal–placental barrier. This must be considered when designing drugs for
women of childbearing age. The maternal–placental barrier is a lipid barrier much like