Antineoplastic Agents Drug Interactions of Clinical Significance

Abstract

With the use of numerous drugs in the treatment of cancer, the potential for drug interactions is considerable. Because of the limited therapeutic indices of anticancer drugs, one should be aware that even small alterations in pharmacokinetics or pharmacodynamics may result in serious adverse effects. Pharmacokinetic drug interactions may alter absorption, bioavailability, distribution, metabolism and elimination patterns. For example, allopurinol inhibits the enzyme xanthine oxidase, thereby blocking the first-pass metabolism of mercaptopurine. Due to this drug interaction, plasma concentrations of mercaptopurine can increase up to 5-fold. Pharmacodynamic drug interactions are characterised by a similar or opposing pharmacological effect of both drugs upon the same biological system. For example, cotrimoxazole (trimethoprim-sulfamethoxazole) inhibits folic acid metabolism through direct binding to dihydrofolate reductase, an enzyme which is also inhibited by methotrexate. More pharmacological investigations are needed to understand the mechanisms and clinical implications of drug interactions with antineoplastic agents.

From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

“…Those patients with impaired renal function are at risk of increased toxicity. Other risk factors include the accumulation of third space fluids [50] and the simultaneous use of non-steroidal anti-inflammatory agents [51], reviewed in [52] and [53]. When given at high doses, i.e.…”

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

“…Up to 10% of all admissions in general hospitals are caused by improper use of drugs and combinations of drugs, resulting in potentially severe drug-drug interactions [1,2]. Adverse drug reactions can especially be severe when these interactions involve cytotoxic anticancer agents [3,4]. Anticancer drugs are dosed close to the maximum-tolerated dose, and factors affecting the pharmacokinetics may therefore greatly increase the likelihood of development of life-threatening toxicities.…”

Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

“…The oral bioavailibility of 6-MP in man is low and highly variable (Knoester et al, 1993;Meerten et al, 1995), however, this is the usual rout of administration. The mechanism for this variability is not fully known but it may be due to a combination of differences in the rate of absorption, distribution, elimination and first-pass metabolism of drug (Knoester et al, 1993).…”