THE DISTRIBUTION, METABOLISM, AND EXCRETION OF D-TUBOCURARINE CHLORIDE AND RELATED COMPOUNDS IN MAN AND OTHER ANIMALS

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 105; no. 3; pp. 299 - 316
• Main Author: MARSH, D F
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.1952
• Subjects: Biological Transport; Body Fluids; Curare - analogs & derivatives; Old Medline; Tubocurarine; CURARE/derivatives
• ISSN: 0022-3565; 1521-0103

The intravenous injection of small amounts of d-tubocurarine and related compounds produces transient skeletal muscular paralysis. Intramuscular injections of about three times this amount of material produce comparable intensity of effect with longer duration of action. Single head drop doses of d-tubocurarine chloride, d-chondocurarine iodide, and d-tubocurarine dimethylether iodide, when injected rapidly intravenously in rabbits, lose half of their apparent effectiveness in four minutes and have completely disappeared in ten to twelve minutes, as determined by reinjection techniques. Half the amount of a head drop dose can be given every five minutes for as many as ten injections before head drop occurs. To determine if these effects are related to the excretion of the agents, procedures for their colorimetric determination with methyl orange were developed and agents containing isotopic carbon were synthesized. Minimal paralytic doses of these agents were given to rats, guinea pigs, rabbits, and dogs. Rats metabolize large amounts of these agents, although some material is excreted unchanged into the urine along with the degradation products. Some radioactivity appears in the feces and expired air. Attempts to determine any possible specific uptake of the drugs by any particular tissue were not successful and the drugs are apparently distributed universally. No increased localization at neuromuscular junctions could be demonstrated. Guinea pigs do not appreciably degrade d-tubocurarine dimethylether although they do partially metabolize d-chondocurarine and presumably would handle the isomeric d-tubocurarine in a similar manner. The rate of destruction and the rate of excretion are slow and do not account for the brief duration of paralytic action. Experiments were carried out in rabbits with repeated administrations of agent in order to attempt to saturate the animal as maximally as possible without producing respiratory depression. The rate of excretion of material is still low and some slow metabolism also occurs. The radioactive procedures were checked against the colorimetric procedures and were found to agree with regard to unchanged drug but the radioactivity determinations indicate additional material is excreted in the urine that does not couple with the dye. Following intravenous injection of doses of the radioactive agents that produce minimal skeletal muscle paralysis in dogs, 60 to 90 per cent disappears from the blood within 120 seconds. Some unchanged drug appears in the urine almost immediately with 3 per cent of the administered dose excreted unchanged within three minutes and 10 per cent in fifteen minutes. Some radioactive material is excreted that is not the agent administered. Non-labelled d-tubocurarine and d-tubocurarine dimethylether were given intravenously to a man. Similar to the animal determinations, the initial plasma levels reached almost the theoretical maximum immediately and promptly began to diminish. Within less than ten minutes, the plasma level had fallen to two-thirds of its original value; at this time paralysis had disappeared. Excretion of the dimethylether in the urine amounted to a cumulated total of 55 per cent in two hours while only 30 per cent of the d-tubocurarine had appeared in this time. The transient nature of the paralytic action of the usual dose of these agents is due to rapid redistribution and is not primarily related to the rate of metabolism or rate of excretion. With repeated doses, or with large doses that will saturate the indifferent depot, the paralytic effects are prolonged and become dependent on the rate of metabolism and excretion.