Dangerous partners. A new highly-throughput screening test suggested that the fungicide thiabendazole (left) and the bronchodilator theophylline might prove dangerous when taken in combination.

Cytochrome P-450s have an important role in metabolic processes of many species, including microorganisms and humans. These heme-containing proteins transform a wide range of substrates into material that is easily excreted.

However, the action of the P-450 system is not always beneficial. It can have a significant impact on indirect drug–drug interactions through enzyme cross-inhibition.

Consequently, the P-450 system is the basis of various in vitro HPLC-based assays traditionally used by many pharmaceutical companies to evaluate the potential for in vivo incompatibility of test drugs. Although useful, this type of analysis is expensive and laborious.

A new, more efficient high-throughput screening (HTS) methodology has been developed, which uses P-450 substrates that produce fluorescent metabolites. Now, a team of researchers has demonstrated a good correlation between these two approaches in a comparative study (Drug Metab. Dispos. 2001, 29, 30–35). They applied the HTS fluorescent technique to screen 29 clinically important antiparasitic drugs for adverse interactions. Although most of the drugs studied were predicted not to pose a risk in multiple-drug therapy, the researchers found that the use of thiabendazole/theophylline and primaquine/antipyrine combinations could result in undesired interactions. Additionally, it has been found that amodiaquine might interact with co-administered antipsychotic drugs.