PHARMACOKINETICS OF QUININE, CHLOROQUINE AND AMODIAQUINE - CLINICAL IMPLICATIONS

Malaria is associated with a reduction in the systemic clearance and a pparent volume of distribution of the cinchona alkaloids; this reducti on is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha(1)-acid glycoprotein, and elim ination half-lives (in healthy adults quinine t(1/2z) = 11 hours, quin idine t(1/2z) = 8 hours) are prolonged by 50%. Systemic clearance is p redominantly by hepatic biotransformation to more polar metabolites (q uinine 80%, quinidine 65%) and the remaining drug is eliminated unchan ged by the kidney. Quinine is well absorbed by mouth or following intr amuscular injection even in severe cases of malaria (estimated bioavai lability more than 85%). Quinine and chloroquine may cause potentially lethal hypotension if given by intravenous injection. Chloroquine is extensively distributed with an enormous total apparent volume of dist ribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than eliminat ion processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be give n either by continuous intravenous infusion, or by frequent intramuscu lar or subcutaneous injections of relatively small doses. Oral bioavai lability exceeds 75%. Amodiaquine is a pro-drug for the active antimal arial metabolite desethylamodiaquine. Its pharmacokinetic properties a re similar to these of chloroquine although the Vd is smaller (17 to 3 4 L/kg) and the terminal elimination half-life is 1 to 3 weeks.