Studies on the Chemotherapy of the Human Malarias. Viii. The Physiological Disposition of Pamaquine 123

Abstract

The recent appreciation (1, 2) of the earlier studies on the curative activity of pamaquine in mosquito-transmitted vivax malaria (3) has promoted renewed interest in the chemotherapeutic potentialities of this compound and of several related derivatives of 8-aminoquinoline. Consequently, a report on the physiological disposition of pamaquine seemed desirable. METHODS AND MATERIALThe individuals used in these studies were, for the most part, patients with central nervous system syphilis. Certain of the pharmacological studies were carried out in normal volunteers. Pamaquine disposition was usually studied prior to induction of therapeutic malaria or after convalescence had become well established. Some of the data on the relationship of dosage5 to plasma drug level, however, were obtained during the course of treatment for acute vivax or falciparum malaria. The chemical methods used have been described elsewhere (4). RESULTS I. Physiological dispositionA. Absorption. The absorption of pamaquine from the gastro-intestinal tract cannot be -examined by balance experiments since the compound

Plasma kinetics and urinary excretion of primaquine in man.

“…Workers in the late 1940s and 1950s showed that pamaquine (Zubrod, Kennedy & Shannon, 1949) and pentaquine (Elderfield & Smith, 1953) were rapidly removed from the body and almost entirely metabolized. These studies, however, suffered from a lack of specific and sensitive techniques.…”

The Therapeutic Effectiveness of Large Doses of Paludrine in Acute Attacks of Sporozoite-Induced Viv Ax Malaria (Chesson Strain) 1

“…The mechanism responsible for this effect is unknown. It is of interest to note that quinacrine has a similar effect on the concentration of pamaquin in plasma (17).…”

Review: Improving the Therapeutic Index of 8-Aminoquinolines by the Use of Drug Combinations: Review of the Literature and Proposal for Future Investigations

“…Pamaquine exposure seems to be increased by the coadministration of quinacrine. 18 In four patients, pamaquine concentrations after coadministered drug were at least six times the level before quinacrine was administered, and the half-lives approximately quadrupled. Clayman and others 16 found a dose-related decrease in primaquine concentrations with coadministration with quinine from no apparent effect at 22.5 mg to a 50% reduction at 120 mg primaquine.…”

“…After oral dosing of pamaquine in humans, peak serum levels are achieved at approximately 3 hours, and then, they decline with a half-life of approximately 2 hours. 18 Zubrod and others 18 also commented that the "pathway of metabolism of the drug is not known. [There is e]vidence for the presence of two metabolic intermediates."…”

“…[There is e]vidence for the presence of two metabolic intermediates." 18 These two metabolites were not identified but would likely represent products of cytochrome P450 or oxidative deamination pathways. Armer and others 19 found that the activity of pentaquine against coccidian parasites was inhibited by monoamine oxidase inhibitors but not cytochrome P450 inhibitors, 19 suggesting that one of the products of this pathway may mediate the drug's antiparasitic effect.…”