Cytochromes and cytokines: Changes in drug disposition in animals during an acute phase response: A mini-review

Diseases are a major cause of variation in drug response. Although many dif ferent diseases are known that have an effect-on the pharmacokinetics or so metimes the pharmacodynamics of a drug, disorders associated with a so-call ed acute phase response (APR) are the most important in this respect. Durin g APR, for example caused by tissue damage or invasion of a pathogen, a gro up of symptoms can be observed that often include fever, lassitude, inhibit ion of gastric function and synthesis of acute phase proteins. All phases t hat together determine the pharmacokinetic profile of a drug, absorption, d istribution, metabolism and excretion, can be affected during APR. From a c linical point of view however, the effects on absorption and metabolism are the most relevant. For drugs that are given orally, a slower absorption ra te is often observed during APR due to a delayed gastric emptying. Even mor e important from a clinical point of view is the depression of biotransform ation capacity in the liver during APR, especially affecting the enzymes of the cytochrome P450 (CYP450) complex. Although much has become known about the mechanism of this effect, a number of questions remain. Cytokines, nit ric oxide and possibly the enzyme heme oxygenase are playing a role in a co mplex process that depends on a mutual interaction between Kupffer cells (m acrophages) and hepatocytes in the liver. The clinician should be aware of unexpected changes in drug effects or residue levels due to cumulation of t he compound during disease or after vaccination. In these situations, drugs that are excreted unchanged may be better alternatives.