DRUG MOLECULES: STRUCTURE AND PROPERTIES 15active at an oral dose of 0.1 mg, then fillers are necessary to ensure that the pill is large
enough to be seen and handled. Additional excipientadditives are required to permit the
pill to be compressed into a tablet (binders), to pass through the gastrointestinal tract
without sticking (lubricants), and to burst open so that it can be absorbed in the small
intestine (disintegrants). Fillers include dextrose, lactose, calcium triphosphate, sodium
chloride, and microcrystalline cellulose; binders include acacia, ethyl cellulose, gelatin,
starch mucilage, glucose syrup, sodium alginate, and polyvinyl pyrrolidone; lubricants
include magnesium stearate, stearic acid, talc, colloidal silica, and polyethylene glycol;
disintegrants include starch, alginic acid, and sodium lauryl sulphate. The importance
of this design consideration follows a 1968 Australasian outbreak of phenytoin drug
toxicity caused by the replacement of an excipient in a marketed formulation of an anti-
seizure drug called phenytoin; the new excipient chemically interacted with the phenytoin
drug molecule, ultimately producing toxicity.
1.1.2.2 Pharmacokinetic Phase
Once the drug molecule has been released from its formulation, it enters the pharma-
cokinetic phase. This phase covers the time duration from the point of the drug’s
absorption into the body until it reaches the microenvironment of the receptor site.
During the pharmacokinetic phase, the drug is transported to its target organ and to
every other organ in the body. In fact, once absorbed into the bloodstream, the drug is
rapidly transported throughout the body and will have reached every organ in the body
within four minutes. Since the drug is widely distributed throughout the body, only a
very small fraction of the administered compound ultimately reaches the desired target
organ—a significant problem for the drug designer. The magnitude of this problem can
be appreciated by the following simple calculation. A typical drug has a molecular
weight of approximately 200 and is administered in a dose of approximately 1 mg; thus,
1018 molecules are administered. The human body contains almost 10^14 cells, with each
cell containing at least 10^10 molecules. Therefore, each single administered exogenous
drug molecule confronts some 10^6 endogenous molecules as potential available receptor
sites—the proverbial “one chance in a million.”
In addition to this statistical imbalance, the drug molecule also endures a variety of
additional assaults during the pharmacokinetic phase. While being transported in the
blood, the drug molecule may be bound to blood proteins. The degree of protein binding
is highly variable. Highly lipophilic drugs do not dissolve well in the aqueous serum and
thus will be highly protein bound for purposes of transport. If a person is taking more than
one drug, various drugs may compete with each other for sites on the serum proteins.
Human serum albumin (HSA) is one of the proteins commonly involved in drug trans-
portation. Table 1.3 gives the percentage protein binding for a diversity of common drugs.
During this transport process, the drug is exposed to metabolic transformations that
may chemically alter the integrity of its chemical structure. This metabolic attack is most
likely to occur during passage through the liver. In fact, some drug molecules are com-
pletely transformed to biologically inactive metabolites during their first pass through the
liver; this is the so-called first pass effect.A complete first pass effect renders a drug
molecule useless since it is metabolically transformed to an inactive form prior to reaching