2.

Drug distribution interactions

(a) Protein-binding interactions

After absorption, drugs are rapidly distributed around the body by the circulation. Some
drugs are totally dissolved in the plasma water, but many others are transported with some
proportion of their molecules in solution and the rest bound to plasma proteins, particularly the
albumins. The extent of this binding varies enormously but some drugs are extremely highly
bound. For example, dicoumarol has only four out of every 1000 molecules remaining unbound
at serum concentrations of 0.5 mg%. Drugs can also become bound to albumin in the interstitial
fluid, and some, such as digoxin, can bind to the heart muscle tissue.

The binding of drugs to the plasma proteins is reversible, an equilibrium being

established between those molecules that are bound and those that are not. Only the unbound
molecules remain free and pharmacologically active, while those that are bound form a
circulating but pharmacologically inactive reservoir which, in the case of drugs with a low
extraction ratio, is temporarily protected from metabolism and excretion. As the free molecules
become metabolised, some of the bound molecules become unbound and pass into solution to
exert their normal pharmacologicalactions, before they, in their turn are metabolised and
excreted.

Depending on the concentrations and their relative affinities for the binding sites, one
drug may successfully compete with another and displace it from the sites it is already
occupying. The displaced (and now active) drug molecules pass into the plasma water where
their concentration rises. So for example, a drug that reduces the binding from 99% to 95%
would increase the unbound concentration of free and active drug from 1% to 5% (a fivefold
increase). This displacement is only likely to raise the number of free and active molecules
significantly if the majority of the drug is within the plasma rather than the tissues, so that only
drugs with a low apparent volume of distribution (V) will be affected. Examples include the
sulfonylureas, such as tolbutamide (96% bound, Vd 10 litres), oral anticoagulants, such as
warfarin (99% bound, Vd 9 litres), and phenytoin (90% bound, Vd 35 litres). However, another
important factor is clearance. Clinically important protein-binding interactions are unlikely if
only a small proportion of the drug is eliminated during a single-passage through the eliminating
organ (low-extraction ratio drugs), as any increase in free fraction will be effectively cleared.
Most drugs that are extensively bound to plasma proteins and subject to displacement reactions
(e.g. warfarin, sulfonylureas, phenytoin, methotrexate, and valproate) have low-extraction ratios,
and drug exposure is therefore independent of protein-binding.

An example of displacement of this kind happens when patients stabilized on warfarin

are given cloral hydrate because its major metabolite, trichloroacetic acid, is a highly bound
compound that successfully displaces warfarin. This effect is only very short-lived because the
now free and active warfarin molecules become exposed to metabolism as the blood flows
through the liver, and the amount of drug rapidly falls. This transient increase in free warfarin
levels is unlikely to change the anticoagulant effect of warfarin because the clotting factor
complexes that are produced when warfarin is taken have a very long half-life, and thus take a
long time to reach a new steady state. Normally no change in the warfarin dose is needed.

In vitro many commonly used drugs are capable of being displaced by others but in the
body the effects seem almost always to be buffered so effectively that the outcome is not
normally clinically important. It would therefore seem that the importance of this interaction
mechanism has been grossly over-emphasised. It is difficult to find an example of a clinically
important interaction due to this mechanism alone. It has been suggested that this interaction
mechanism is likely to be important only for drugs given intravenously that have a high-
extraction ratio, a short pharmacokinetic-pharmacodynamic half-life and a narrow therapeutic
index. Lidocaine has been given as an example of a drug fitting these criteria. Some drug
interactions that were originally assumed to be due to changes in protein binding have
subsequently been shown to have other interaction mechanisms involved. For example,
inhibition of metabolism has subsequently been shown to be important in the interactions
between ‘warfarin and phenylbutazone’,and ‘tolbutamide and sulfonamides’,

However, knowledge of altered protein binding is important in therapeutic drug

monitoring. Suppose for example a patient taking phenytoin was givena drug that displaced
phenytoin from its binding sites. The amount of free phenytoin would rise but this would be
quickly eliminated by metabolism and excretion thereby keeping the amount of free active
phenytoin the same. However, the total amount of phenytoin would now be reduced. Therefore if
phenytoin was monitored using an assay looking at total phenytoin levels it may appear that the
phenytoin is subtherapeutic and that the dose may therefore need increasing. However, as the
amount of free active phenytoin is unchanged this would not be necessary and may even be
dangerous.

Basic drugs as well as acidic drugs can be highly protein bound, but clinically important
displacement interactions do not seem to have been described. The reasons seem to be that the
binding sites within the plasma are different from those occupied by acidic drugs (alpha-1-acid
glycoprotein rather than albumin) and, in addition, basic drugs have a large V with only a small
proportion of the total amount of drug being within the plasma.

(b) Induction or inhibition of drug transporter proteins

It is increasingly being recognised that distribution of drugs into the brain, and some
other organs such as the testes, is limited by the action of drug transporter proteins such as P-
glycoprotein. These proteins actively transport drugs out of cells when they have passively
diffused in. Drugs that are inhibitors of these transporters could therefore increase the uptake of
drug substrates into the brain, which could either increase adverse CNS effects, or be beneficial.