Pharmacokinetic variation

Pharmacokinetic variability results from differences between patients in the absorption, distribution, elimination and metabolism of a drug. Thus, a given dose may produce different drug concentration profiles against time in individual patients. The importance of pharmacokinetic variability in any situation depends on the mechanisms normally responsible for distribution and elimination of a particular drug, the possible influence of patient characteristics or co-administered drugs on these mechanisms, and the therapeutic margin of the drug. Gastrointestinal absorption may be slowed by atropine or opiates, or accelerated by metoclopramide, which hastens gastric emptying. Muscle mass is greater and adipose tissue mass smaller in men than in women. Thus, water-soluble drugs have larger distribution volumes in men and lipid-soluble drugs (e.g. diazepam, propranolol) have larger distribution volumes in women. Highly extracted drugs (e.g. propofol, propranolol) with clearance close to hepatic blood flow are sensitive to changes in hepatic blood flow, whereas enzyme induction or inhibition, or changes in protein binding have minimal effect. The opposite is true for low extraction drugs (e.g. phenytoin, warfarin). The clearance of renally excreted drugs is decreased in patients with renal failure. In elderly patients, the usual trend is a decrease in central volume of distribution and clearance. In general terms, drug dosage can be reduced if drug distribution or clearance are decreased, and increased if changes in the opposite direction are anticipated. Changes in central volume of distribution influence peak concentrations obtained, whereas clearance has a greater effect on rate of decline in blood concentration and maintenance dose requirement.