Therapeutic drug monitoring of antimetabolic cytotoxic drugs

Therapeutic drug monitoring is not routinely used for cytotoxic agents. The re are several reasons, but one major drawback is the lack of established t herapeutic concentration ranges. Combination chemotherapy makes the establi shment of therapeutic ranges for individual drugs difficult, the concentrat ion-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protoc ols for many classes of cytotoxic compounds exist in specialized centres, a nd some of these protocols are now part of large multicentre trials. Noneth eless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite thera py, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic en zyme activities or genotype in addition to, or instead of, the more traditi onal measurement of parent drug or drug metabolites. The cytotoxic activiti es of mercaptopurine and fluorouracil are regulated by thiopurine methyltra nsferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. La ck of TPMT functional activity produces Life-threatening mercaptopurine mye lotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioava ilability, pharmacokinetics, toxicity and efficacy of their substrate drugs .