Pharmacokinetics and kinetic-dynamic modeling of an 8-aminoquinoline candidate anticyanide and antimalarial drug (WR242511).
Malaria is a major cause of health problems in a large portion of the world. The 8-aminoquinoline compound, primaquine, is one of the only compounds useful for relapses of Plasmodium vivax and Plasmodium ovale malaria. Primaquine has several toxicities that include methemoglobinemia and hemolytic anemia. The induction of methemoglobinemia is a treatment for cyanide poisoning. We studied the pharmacokinetics and pharmacodynamics (percentage methemoglobin) for WR242511, an 8-aminoquinoline primaquine replacement and potential anticyanide compound. The drug's pharmacokinetics and pharmacodynamics are described for oral and intravenous dosing, and two kinetic-pharmacodynamic models are shown to describe the single dose data. A significant lag occurs between the onset of appearance of drug in the plasma and the onset of methemoglobinemia. Peak drug concentrations occurred within 4 hr for oral dosing, and peak effect (percentage methemoglobin) did not occur for 72-96 hrs for both the oral and intravenous routes. Elimination half-life for the drug was 30 +/- 14 hr. Two kinetic-dynamic models, one with an effect compartment relating drug concentration to effect and one with metabolite causing a first-order conversion of hemoglobin to methemoglobin, are compared as to their ability to predict multiple dose pharmacokinetics and pharmacodynamics. Both models were useful in predicting drug concentrations and methemoglobin levels for multiple-dose experiments.
Marino
M T
MT
Department of Pharmacology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Peggins
J O
JO
Brown
L D
LD
Urquhart
M R
MR
Brewer
T G
TG
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D004334:Drug Administration Schedule; D007275:Injections, Intravenous; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D008722:Methods; D008954:Models, Biological; D010599:Pharmacokinetics; D011319:Primaquine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity
D000962:Antimalarials; C068820:WR 242511; D008706:Methemoglobin; D011319:Primaquine