Pharmacokinetic interactions of antimalarial agents

Combination of antimalarial agents has been introduced as a response to wid espread drug resistance. The higher number of mutations required to express complete resistance against combinations may retard the further developmen t of resistance. Combination of drugs, especially with the artemisinin drug s, may also offer complete and rapid eradication of the parasite load in sy mptomatic patients and thus reduce the chance of survival of resistant stra ins. The advantages of combination therapy should be balanced against the increa sed chance of drug interactions. During the last decade, much of the pharma cokinetics and metabolic pathways of antimalarial drugs have been elucidate d, including the role of the cytochrome P450 (CYP) enzyme complex. Change i n protein binding is not a significant cause of interactions between antima larial agents. CYP3A4 and CYP2C19 are frequently involved in the metabolism of antimalarial agents. Quinidine is a potent inhibitor of CYP2D6, but it appears that this enzyme does not mediate the metabolism of any other antim alarial agent. The new combinations proguanil-atovaquone and chlorproguanil -dapsone do not show significant interactions. CYP2B6 and CYP3A4 are involved in the metabolism of artemisinin and derivat ives, but further studies may reveal involvement of more enzymes. Artemisin in may induce CYP2C19. Several artemisinin drugs suffer from autoinduction of the first-pass effect, resulting in a decline of bioavailability after r epeated doses. The mechanism of this effect is not yet clear, but induction by other agents cannot be excluded. The combination of artemisinin drugs w ith mefloquine and the fixed combination artemether-lumefantrine have been studied widely, and no significant drug interactions have been found. The a rtemisinin drugs will be used at an increasing rate, particularly in combin ation with other agents. Although clinical studies have so far not shown an y significant interactions, drug interactions should be given appropriate a ttention when other combinations are used.