Pharmacokinetics

Pharmacokinetics refers to the way in which drugs are dealt with by the human body. Drugs are broken down, absorbed and cleared from the body through numerous chemical reactions and processes, described in more detail below.

The amount of drug that is absorbed into the body and is active against an infection may vary due to a range of factors: consumption of food, drinks and other drugs, correct dosing, and individual variation. If a drug does not reach sufficient levels in the blood, it may not be active against an infection. Studies of anti-HIV drugs have shown that low blood levels of certain drugs have been predictive of poor long-term outcome.

Drug interactions

When two or more different drugs are taken together, an effect other than that achieved with the single drug may result. One drug may increase or decrease the amount of another drug that is absorbed into the body. If you are taking several different drugs, check with your doctor whether there are interactions that affect how you take them. For example, it can be important to leave a couple of hours between taking certain drugs. Combining drugs that can cause similar side-effects, such as two drugs that cause peripheral neuropathy, for example, should only be done with caution.

Types of drug interaction

Drug interactions are usually divided into four groups: antagonism, synergism, potentiation and interaction with metabolism.

Antagonism means that one drug reduces or blocks the effect of another. There are various ways in which this can happen. For instance, drugs can interfere with each other's absorption in the gut, circulation in the blood or uptake by cells.

Synergism means that two or more drugs work together against one target, producing an effect that is greater than the individual effects of the drug added together (like combining two plus two and getting five). Synergistic interactions can be beneficial, and treatments may be deliberately chosen for this effect; for example, many anti-HIV drug combinations seem to be synergistic in their effects against the virus.

Potentiation means that drug A boosts the effects of drug B, often by increasing the levels of drug B in the blood. Like synergism, this may be useful in cases in which the beneficial effects of drug B are enhanced. However, the toxicities of drug B may also be potentiated, leading to an increased level of side-effects.

Bare in mind that it is not only prescribed medicines that can interact. Food in the stomach can also increase or decrease the absorption of drugs. There may also be interactions between prescribed medicines and recreational drugs, although these are often poorly researched.

How drugs can interact

There are at least five points at which drugs may interact in the body:

• While being absorbed in the stomach and intestines.

• While being processed in the liver.

• While circulating in the bloodstream.

• Within cells.

• While being removed by the kidney.

Altered absorption

Alcohol and some drugs (especially opiates such as morphine and codeine) slow the digestive process and therefore slow absorption of the drug from the intestine. Other drugs such as metoclopramide speed up the process and may increase the speed and extent to which another drug is absorbed.

Some drugs may combine with food or other drugs in the gut to form chelates compounds which are not easily absorbed reducing the effects of the drug. An example of this is the tetracycline group of antibiotics which form chelates with calcium in milk or certain antacids and thereby produce minimal effect.

An important interaction with the original formulations of ddI (didanosine, Videx) concerns stomach acidity. ddI is broken down by stomach acid and any factors which increase gastric acidity will cause ddI absorption to be reduced. For this reason citrus juices such as orange or grapefruit should not be taken at the same time. Conversely drugs that lower stomach acidity will increase ddI absorption and possibly also increase its toxicity. Examples of drugs that do this are cimetidine (Dyspamet / Tagamet), ranitidine (Zantac) and antacids such as Rennies and magnesium trisilicate. ddI is formulated with a buffer which neutralises the stomach acid and allows the ddI to be absorbed; this will have a negative effect on other drugs which do need stomach acid to be absorbed, including dapsone, ketoconazole (Nizoral) and ciprofloxacin (Ciproxin).

However, a re-formulated version of ddI (enteric coated; VidexEC) which received licensing in 2000 does not require the buffer used in the previous formulation. ddI EC consists of gastro-resistant capsules containing enteric coated beadlets of ddI. Lack of the buffer agent means that ddI EC can be taken with the protease inhibitor indinavir (Crixivan), but still needs to be taken on an empty stomach.

A similar interaction can occur between protease inhibitors and acid-reducing agents, such as ranitidine. Since many protease inhibitors need the stomach to be acidic in order to allow proper drug absorption into the bloodstream, the use of acid-lowering agents can reduce blood levels of protease inhibitors, reducing their anti-HIV activity and increasing the chance of the development of resistance. Many acid-lowering agents are available without prescription and over-the-counter in chemists, so many patients may be unaware of these risks when they buy the drugs to treat heartburn or indigestion. The protease inhibitors most affected appear to be atazanavir (Reyataz), fosamprenavir (Telzir) and indinavir, although there is evidence that ritonavir-boosted lopinavir (Kaletra) has a less severe interaction with acid-reducing agents.

Sustained release (sr) preparations release the active drug slowly whilst travelling through the gut. They can provide a continuous dose of the drug over quite a long period of time. If the patient has diarrhoea the tablet may go through the entire gut without releasing very much of the drug. This can be quite a problem and the form of the drug should be changed to one which is absorbed more readily e.g. use morphine solution instead of morphine sr tablets. The advantage of the sustained release tablet is then lost so the solution has to be given more often.

Effects of liver enzymes

Once a drug has been absorbed in the gut, it passes to the liver where a proportion of the dose may be broken down by enzymes (see below). The most serious drug interactions are likely to be related to the way in which some drugs are processed in the liver by substances called cytochrome P450 enzymes, or isozymes.

These enzymes are found within the cells that make up the liver. Although 23 different P450 enzymes have been identified, researchers have identified five that are particularly important in processing drugs. They work through a process called oxidation, which converts the drug into a slightly different form. Other enzymes may then convert the oxidised drug into a water-soluble form that can be readily excreted in the urine. Each individual P450 enzyme is given a three-character name, such as 1A2, 2C8 or 3A4.

Due to their inherited genetic make-up, some people may produce higher or lower than average amounts of specific P450 enzymes, which may account for person-to-person variations in response to treatments. People with naturally high levels of a certain P450 enzyme may break down a drug faster than average, and thus may not achieve high enough levels of drug in their bodies to be effective. Likewise, people with naturally low levels of a specific P450 enzyme may metabolise a drug slower than average, allowing the drug to reach unusually high levels in their body. For example, about 3% of the white Caucasian population has low levels of the 2D6 enzyme that is involved in breaking down 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). They may experience five to tenfold higher blood levels of MDMA than people with 'normal' levels of 2D6.

Similar effects can be caused by drugs, leading to interactions. Take the example of a person taking two treatments, called Drug A and Drug B. If Drug A causes a reduction in the activity of a specific P450 enzyme, that may make it harder for the body to break down Drug B, leading to an increase in blood levels of Drug B. Similarly, if Drug A causes an increase in the level of a specific P450 enzyme, that might help the body to metabolise Drug B more quickly, leading to lower blood levels of Drug B. For example, St Johns wort induces several P450 enzymes used to metabolise key anti-HIV drugs. This may lead to very low levels of drugs such as indinavir, nelfinavir (Viracept), saquinavir (Invirase / Fortovase), nevirapine (Viramune) and efavirenz (Sustiva).

Other interactions occur when someone is taking two drugs which are both broken down by the same P450 enzyme. In effect, there may not be enough of the enzyme to break down both drugs efficiently, allowing one of the drugs to reach unusually high levels in the body.

Researchers have identified which P450 enzymes are involved in breaking down specific drugs, as well as which drugs induce (increase) or inhibit (decrease) the effects of specific enzymes. This allows them to predict when an interaction between two drugs is likely to happen, even though there may have been no studies in which people took both drugs under controlled conditions.

A number of case studies have reported sexual dysfunction in men taking a range of medications including protease inhibitors. Doctors have suggested that this sexual dysfunction may be due to the interaction of protease inhibitors and liver enzymes, leading to increased oestrogen levels.

Protein binding

Once they have reached the bloodstream, some drugs bind tightly to proteins in the blood such as albumin. In this form they are usually inactive, and are quickly removed from the body. If a drug is highly protein-bound in this way, the dose is carefully chosen so that a large enough proportion of each dose remains unbound and active in the body.

Some drugs are far more protein-bound than others. If you take two highly protein-bound drugs called Drug X and Drug Y, Drug X may bind to most of the available protein in the blood, leaving little protein left to bind to Drug Y. That can mean that an unusually high proportion of each dose of Drug Y is left unbound and active - perhaps the equivalent of taking an overdose of Drug Y.

Excretion via the kidney

Some drugs are wholly or partially eliminated through the kidney. Any other drug that interferes with this may increase or decrease the blood levels of the first drug. For example, probenecid will decrease the amount of AZT (zidovudine, Retrovir) excreted in the urine and increase the blood levels and effects. This may be useful as the number of AZT capsules taken daily can be decreased when taken in combination with probenecid, thus decreasing drug costs.

Receptor effects

Drugs work in the body by acting on what is known as a receptor. An analogy is a lock and key, in which the drug (the key) fits a specific receptor (the lock). If two drugs are present in the body that both use the same receptor, it is possible that due to competition one or both may not have an effect, as though one key is in the lock preventing the other from being inserted.

Additive toxicity

Combinations of drugs may result in greater toxicity than would be seen with single drugs. For example, either AZT or ganciclovir (Cymevene) used on its own has a suppressive effect on the bone marrow that decreases its ability to form red and white blood cells and platelets. If these drugs are taken at the same time, the toxic effects on the bone marrow are increased, and anaemia or neutropenia may develop. Other drugs which can cause serious bone marrow inhibition when taken with AZT include co-trimoxazole (Bactrim / Septrin), interferon, dapsone, pyrimethamine (Daraprim), pentamidine and cytotoxic chemotherapy drugs such as doxorubicin (Caelyx / Myocet).

Other additive toxicities of note are pancreatitis, which can occur with ddI and ddC (zalcitabine, Hivid) and peripheral neuropathy. Alcohol can increase the likelihood of pancreatitis occurring.

Nucleoside reverse transcriptase inhibitor pharmacokinetics

Researchers from the University of Colorado have a proposed a new explanation for why people with advanced HIV disease tend to suffer more serious toxicities when treated with nucleoside reverse transcriptase inhibitors (NRTIs). The theory links pharmacokinetics and the impact of advanced HIV disease.

The researchers have suggested that human cells get exposed to extreme concentrations of NRTIs during advanced HIV infection because cells are highly activated and this activation causes an over production of nucleoside analogue triphosphates - the active forms of NRTIs within cells. Nucleoside analogue triphosphates are produced at higher levels when cells are activated due to greater production within the cell of the kinases that carry out the breakdown of NRTIs into this active form.

Nucleoside analogue triphosphates disrupt HIV replication by competing with nucleotides for incorporation into viral DNA, but they also become incorporated into the DNA of mitochondria within human cells. This causes loss of efficiency in mitochondria, leading to reduced cellular efficiency and malfunction (Anderson 2004). Mitochondrial toxicity is thought to be a causal factor in side-effects such as peripheral neuropathy, pancreatitis and fat wasting.

If this theory is correct, it may also explain the increased toxicity seen in people coinfected with HIV and hepatitis C who are receiving concurrent treatment. Therapy for hepatitis C comprises interferon alfa (IntronA / Roferon-A / Viraferon) or peginterferon alfa (Pegasys / PegIntron / ViraferonPeg) - an immune stimulant - and ribavirin (Copegus / Rebetol / Virazole). Immune activation due to interferon alfa may increase cellular levels of NRTIs, inducing or worsening side-effects.

Reference

Anderson PL et al. The cellular pharmacology of nucleoside- and nucleotide analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities. Clin Infect Dis 38: 743-753, 2004.