Abstract
This investigation has dealt with the absorption, excretion, and metabolism of Daraprim in the rhesus monkey and with the tissue distribution and toxicity of this drug in both the monkey and the white rat. Following is a summary of the most pertinent observations.
1. Absorption, excretion, metabolism, and tissue distribution. Studies on the concentrations of "Daraprim" in plasma following single doses, have demonstrated that the drug is absorbed rather slowly from the gastrointestinal tract; thus the dose of drug markedly influences the time at which peak plasma levels are attained. Although in general the height of the plasma level was proportional to dose, there were large variations in levels of individual monkeys receiving the same dose.
Repeated plasma level determinations on monkeys which received Daraprim at doses of 1.25 to 20 mgm./kgm. for three to forty-two days showed that the drug did not accumulate in plasma except when animals were moribund.
Balance studies on monkeys which had received Daraprim either orally or intramuscularly indicated that the drug undergoes extensive metabolism. At the most, the equivalent of only 20 per cent of the drug administered could be recovered from the urine. Spectrographic and countercurrent distribution studies indicated that even this 20 per cent contained metabolic products of Daraprim as well as unchanged drug.
The above balance studies also indicated that absorption of Daraprim from the gastrointestinal tract is essentially complete, for urinary elimination was the same irrespective of route of administration.
Studies on both rat and monkey have shown that "Daraprim" is localized to a moderate degree in certain tissues particularly in lung, liver, kidney, and spleen. The amount of drug found in any tissue was directly proportional to dose; there was no indication of excessive accumulation except when animals were moribund. At any given dose tissues of the rat contained far less "Daraprim" than those of the monkey. However, essentially identical tissue concentrations were found in both species at doses which evoked equal toxicity.
Comparative studies on the tissue distribution of Daraprim, chlorguanide, and chloroquine in the rat showed that at a given dose tissue concentrations of the above pyrimidine were slightly greater than those of chlorguanide but far less than those of chloroquine. Due to the extensive localization of chloroquine in most tissues, the disparity between Daraprim and the latter drug increased with dosage.
2. Toxicity. When administered to the growing rat at repeated daily closes approximating 190 mgm./kgm., Daraprim was almost uniformly fatal. Daily doses approximating 100 mgm./kgm. suppressed growth markedly hut were not lethal ; doses of 50 mgm./kgm. or less did not affect growth or survival. Comparative studies showed that, with respect to either lethality or growth suppression, Daraprim was approximately one-half as toxic as chlorguanide and one-half to one-third as toxic as chloroquine.
When administered to rats in doses of 190 mgm./kgm. for three weeks or longer Daraprim produced skin lesions, marked leucopenia and neutropenia, and exhaustion of myeloid elements of femoral marrow. These effects were totally unlike reactions to fatal intoxication with either chlorguanide or chloroquine.
Daraprim was almost uniformly fatal to the rhesus monkey when administered in repeated daily doses of 5 mgm./kgm. and greater; one of four animals succumbed to daily doses of 2.5 mgm. Thus with respect to lethal action this pyrimidine is at least sixteen times as toxic as chloroquine or chlorguanide. The data also indicate that Daraprim is more than forty times as toxic for the monkey as the rat.
Symptoms of fatal Daraprim intoxication in the monkey were of two types; acute convulsive seizures, and slowly progressing intoxication characterized by muscular weakness, malaise, anorexia, diarrhea, bronze pigmentation of the skin on the face and chest, gingivitis, and dehydration. The convulsant action of Daraprim was most prominent at doses of 20 mgm./kgm. but iii two instances occurred at doses of 10 mgm. The less acute manifestations of Daraprim intoxication appeared in an unpredictable manner at doses of 2.5 to 20 mgm.
Monkeys which succumbed to Daraprim, yet survived treatment for seven or more days, exhibited a striking leucopenia with agranulocytosis. Fatal Daraprim intoxication evoked serious lesions in the spleen, lymph nodes, adrenal cortex, bone marrow, and kidney calyx. The microscopic characteristics of these lesions were described in detail.
The above toxicological data were evaluated in relation to preliminary findings in other animal species, including man, and were interpreted as presenting a serious potential hazard to the human user. In view of current availability of effective and well tolerated drugs, it was concluded that general use of an agent with the toxicological characteristics of Daraprim could not be justified unless rigidly controlled studies in man demonstrated that the drug had unique antimalarial properties at doses which would convey a wide margin of safety.
Footnotes
- Received September 4, 1952.
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