Pharmacokinetics of Quinine, Chloroquine and Amodiaquine

Abstract

Malaria is associated with a reduction in the systemic clearance and apparent volume of distribution of the cinchona alkaloids; this reduction is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha 1-acid glycoprotein, and elimination half-lives (in healthy adults quinine t1/2z = 11 hours, quinidine t1/2z = 8 hours) are prolonged by 50%. Systemic clearance is predominantly by hepatic biotransformation to more polar metabolites (quinine 80%, quinidine 65%) and the remaining drug is eliminated unchanged by the kidney. Quinine is well absorbed by mouth or following intramuscular injection even in severe cases of malaria (estimated bioavailability 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 distribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than elimination processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be given either by continuous intravenous infusion, or by frequent intramuscular or subcutaneous injections of relatively small doses. Oral bioavailability exceeds 75%. Amodiaquine is a pro-drug for the active antimalarial metabolite desethylamodiaquine. Its pharmacokinetic properties are similar to these of chloroquine although the Vd is smaller (17 to 34 L/kg) and the terminal elimination half-life is 1 to 3 weeks.

Chloroquine pharmacokinetics in pregnant and nonpregnant women with vivax malaria

“…CQ has unusual pharmacokinetic properties. It has very long terminal half-life and an enormous Vd [14,10,11]. Previous pharmacokinetic studies in pregnancy measured plasma concentrations, which has limitations, as CQ is concentrated in platelets and granulocytes and then variably released from these cells in blood samples [15].…”

Diversity and severity of adverse reactions to quinine: A systematic review

“…Among the individual patient reports, we reviewed both immune-mediated and dosedependent, toxic adverse reactions. The adverse reactions reported in group data were toxic reactions, related to the narrow margin between therapeutic and toxic blood levels [8,9]. Dose-dependent toxic reactions, often described as cinchonism [8], are well known, typically mild and reversible.…”

“…Immune-mediated reactions were defined a priori as exposure to a therapeutic dose of quinine (or less, as in a quinine-containing beverage or lotion) daily for <4 weeks [7] or taken only intermittently. Toxic reactions were defined a priori as exposure to more than 2 g of quinine in <24 hr, or a serum quinine concentration more than 10 mg ml 21 [8,9]. Reports that did not fulfill criteria for either idiosyncratic or toxic reactions were excluded.…”

A case of acute interstitial nephritis and granulomatous hepatitis induced by ingesting quinine

“…In a previously reported case of quinine-induced AIN, the patient also ingested quinine for leg cramp, not for malaria [2]. There may be reason to believe that the pharmacokinetics of quinine may change according to the severity of malarial infection [22]. As reviewed by Silamut et al, the high levels of plasma a 1 -acid glycoprotein produced in severe malaria may prevent toxicity by binding to the drug and thereby reducing the free fraction of quinine [23].…”