A B S T R A C T Tryptophol (3-indole ethanol) is a compound which induces sleep, and is formed: (a) in the liver after disulfiram treatment, and (b) by the parasite in trypanosomal sleeping sickness. We prepared, purified, and characterized radiolabeled tryptophol for the purpose of defining its tissue distribution in animals. Tryptophol was found to be highly lipophilic, with an octanol: water partition coefficient of 29.8. Brain extraction, determined after intracarotid injection, was high (brain uptake index = 117+3.5%), and nonsaturable, suggesting the absence of a carrier system. After intravenous administration, tryptophol distribution to tissues correlated with relative blood flow. More than 85% of the radioactivity remaining in brain 2-5 min after intravenous injection co-migrated with tryptophol standards when analyzed by thin-layer chromatography. Other evidence suggested that tryptophol binds to serum and in vivo may be stripped from serum albumin and taken up by brain in a single capillary transit. Our study suggests that in states such as trypanosomal sleeping sickness or disulfiram treatment, remotely formed tryptophol gains ready access to brain (it is 100% cleared in a single capillary passage), and could thus cause somnolence.

3-Indole ethanol has been recently identified as the hypnotic agent in trypanosomal sleeping sickness, and because it is formed in vivo after ethanol or disulfiram treatment, is also associated with the study of alcoholism. When administered intraperitoneally to rats (250 mg/kg) tryptophol induced a sleep-like state that lasted less than an hour (no righting reflex was apparent 2 min after injection, but it returned at 11 min in bovine serum albumin solution, and 47 min in 40% ethanol solution). In ethanol solutions, tryptophol reduced brain cortical glucose utilization by 55% to the basal brain metabolic rate, and this effect lasted less than 1 h. Synergistic effects of tryptophol and ethanol were suggested by the observation that in albumin solution, tryptophol reduced brain glucose utilization by 35%, but a normal rate was not observed until 2 h postinjection.

The double internal standard isotope method (utilizing both a highly diffusible [H3 water] and a nondiffusible reference isotope [113m-indium bound to ethylene diamine tetra-acetic acid]) was applied in studies of C14 glucose uptake in the rodent blood fluke. Schistosomatium douthitti. Uptake of C14-L-glucose was minimal and occurred by a diffusional mechanism alone. Transintegumental uptake of the stereoisomer C14-D-glucose, corrected for passive adsorption of the solute on the external tegumental surface, occurred by a saturable, carrier-mediated mechanism. Kinetic analyses demonstrated that glucose uptake was best described by a carrier system plus a diffusional component. Estimates were derived in male worms for the half-saturation constant (Km - 1.7 +/- 1.0 mM), maximal velocity (Vmax = 10.4 +/- 1.7 nmol.min-1.mg wet wt-1) and diffusional component (Kd = 0.57 microliters.min-1.mg wet wt-1). In females, these measurements (Km = 1.8 +/- 1.4 mM; Vmax = 11.3 +/- 2.2 nmol.min-1.mg wet wt-1; and Kd = 0.60 microliters.min-1.mg wet wt-1) were similar. These parameters were compared with estimates from mammalian tissues, and differences were attributed tentatively to the greater surface area-to-volume ratio of the schistosome.

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