NAPHTHOQUINONE ANTIMALARIALS

XX. Metabolic Degradation

¹ Chemical Laboratory, Harvard University; Surgical Research Laboratory, Beth Israel Hospital, Boston; Department of Surgery, Harvard Medical School

1. A method of evaluating naphthoquinones as possible antimalarial drugs with respect to plasma levels, extent of metabolic deactivation, and persistence of active material following oral or intravenous administration to nonmalarial individuals consists in determination of the antirespiratory activity per colorimetric unit of total naphthoquinone pigment extracted from plasma samples drawn at varying periods of time.

2. Compounds with hydrocarbon side chains terminating in a ring are rapidly metabolized to products hydroxylated in this ring. The metabolites retain 10-60 per cent of the original activity, often persist in the blood for long periods, and in some instances may exert a therapeutic effect.

3. A synthetic compound having a hydroxyl group in a large hydrocarbon side chain shows improved resistance to metabolic deactivation, possesses adequate activity (i.v.), and appears to offer promise as a drug.

4. Of various animals investigated for the laboratory evaluation of new compounds, the mouse shows the closest parallelism to man in the retention and degradation of the naphthoquinones. Drug degradation in vitro was accomplished in a mouse liver homogenate.

5. Intravenous toxicity observed in dogs under certain conditions can be counteracted by adding albumin to the solution injected.