MECHANISMS OF DRUG INTERACTIONS

Drugs are eliminated from the body via the following routes:

a) Renal
b) Hepatic
c) Intestinal
d) Others e.g. skin, lungs

The major routes of elimination are renal and hepatic.

a) Renal elimination

Many drugs are excreted unchanged in the urine. Generally, the clearance of such drugs is directly proportional to renal function.
Very few drugs interact to slow the clearance of other drugs e.g. probenecid. Also, very few drugs accelerate or induce the clearance of drugs through the kidney.

b) Hepatic elimination

Drugs which are metabolised are mainly eliminated from the body through chemical modification (biotransformation) in the liver. The goal of metabolism is to detoxify drugs, and make them either more water soluble (for excretion in the urine) or more fat soluble (for excretion in the bile, and then into the faeces).
The cytochrome P450 enzymes in the liver chemically oxidize or reduce drugs (e.g. through hydroxylation).

2 Major mechanisms of drug interactions

Drugs may interact with each other in two ways:

a) Pharmacokinetic
b) Pharmacodynamic

a) Pharmacokinetic interactions

The most important and most common pharmacokinetic drug interactions involve the following:

i) Inhibition of metabolism
ii) Induction of metabolism
iii) Altered drug absorption
iv) Inhibition of renal excretion
v) Displacement from plasma protein binding sites

Most of the drug interactions discussed in this booklet are pharmacokinetic interactions.

b) Pharmacodynamic interactions

Some drug interactions involve synergism or antagonism of drug effects, without alterations in the concentrations of either drug. This kind of interaction can affect either drug activity or toxicity. These are called pharmacodynamic interactions. An example is enhanced bone marrow suppression in patients given concurrent zidovudine and ganciclovir.

a) The Cytochrome P450 System

The cytochrome P450 enzyme system chemically oxidizes or reduces drugs during the process of metabolism. There are more than 25 human cytochrome P450 enzymes, identified using a particular nomenclature. There are 4 major families, indicated by number, six major subfamilies, indicated by letter, then individual enzymes within a subfamily, also indicated by number. For example, 3A4, 2D6, 2C19.

The origin of the name 'P450' lies in the fact that these cytochromes absorb ultraviolet light in the presence of carbon monoxide at a wavelength of 450 nm.

b) Other hepatic enzymes involved in drug clearance

Besides the cytochrome P450 system, other enzymes are also involved in metabolism. This includes glucuronyl transferases, acetylases, sulfotransferases and proteases.

c) What is a P450 substrate?

A P450 substrate is any drug that is metabolised by one or more of the P450 enzymes (also referred to as 'isoforms'). Most drugs are mainly metabolized by a single P450 enzyme.

There are many P450 enzymes in humans. Only a few of these enzymes are involved in drug metabolism. More than 50% of metabolised drugs are substrates for the 3A4 enzyme. This enzyme is by far the most important for antiretroviral drugs.

d) What is a P450 inhibitor?

A P450 inhibitor is any drug that inhibits the metabolism of a P450 substrate. This occurs because the drug reduces the amount/activity of the P450 enzyme, which leads to inhibition of metabolism. Like most enzymatic inhibition, this process is almost always competitive and reversible. In other words, as soon as the inhibitor is gone, metabolism is back to normal.

Like all enzyme inhibitors, some P450 inhibitors are strong (potent) inhibitors, and others are poor (weak). For example, the approved HIV protease inhibitors are all cytochrome P450 3A4 enzyme inhibitors. However, ritonavir is a potent inhibitor, amprenavir, indinavir and nelfinavir are moderate inhibitors, and saquinavir is a weak inhibitor.
A drug does not have to be a P450 substrate to be an inhibitor. For example, fluconazole is a moderate to weak P450 inhibitor, but is not a P450 substrate - it is primarily cleared renally.

e) What is a P450 inducer?

A P450 inducer increases the amount of the P450 enzyme. It does this by binding directly to elements in the DNA that regulate expression of the gene. By doing this, inducers cause an increase in transcription of the P450 gene and thus increase the amount of enzyme produced. An increase in the amount of enzyme produced implies a more rapid rate of metabolism of drugs that are substrates for that enzyme.

Unlike inhibition, induction persists for several days, even after stopping administration of the inducing drug. This is because the enzymes which have been induced persist for several days following induction.

Inducers can turn on (activate) many genes at once. Thus, an inducer like ritonavir can increase the amount of not only P450 3A4 and 2D6, but also the amount of glucuronyl transferase. This is the reason why ritonavir and nelfinavir reduce concentrations of glucuronyl transferase substrates like zidovudine, as well as P450 substrates like ethinyl estradiol.

Some drugs are potent inducers, while others are moderate or weak inducers. Rifampin and phenobarbital are two of the most potent inducers. Ritonavir, nelfinavir, efavirenz and nevirapine are moderate P450 inducers.