1. The method described by Jalon for estimating
tubocurarine by its action on the frog's rectus
abdominus, was adopted for determining the drug
equivalent of tissue extracts and biological fluids.
This method was used to follow the fate of the drug
in man and animals.
2. The immediate volume of distribution on intravenous injection corresponds to the plasma volume.
The drug does not enter the blood cells. It disappears from the plasma exponentially with a halving
time of about thirteen minutes. These conclusions
apply both to man and to rabbits.
3. In the conscious human subject, a concentration
of 4μg. per ml. in the plasma causes complete paralysis. A concentration of 1µg. per ml. has very
little effect.
4. About 20-40% of the drug appears in the urine.
This percentage may be increased by water diuresis.
Excretion continues for several hours, even when the
paralysis only lasts about half an hour.
5. The main route of disappearance of the drug from
the body does not depend on the kidneys, since
double nephrectomy in rats did no more than
slightly delay full recovery from paralysis.
By extracting whole mice, it was shown that
about 60% of the dose was inactivated in the body
within four hours.
Since subtotal hepatectomy in rats did not appreciably affect the duration of paralysis, the
liver is probably not the main site of inactivation. It is possible that inactivation occurs
in voluntary muscles, which were found to contain
40% of the dose in an experiment on rabbits.
6. The effective dose by oral administration in
rats is about 100 times the effective dose by
intramuscular administration. Absorption occurs
in the small intestine but not in the stomach.
On intravenous injection, appreciable quantities
(12% of the dose) may be excreted in the stomch.
7. A rapid intravenous injection of tubocurarine
usually causes bronchoconstriction in guinea-pigs.
A second injection has no such effect.
The effect may be prevented or interrupted by
neoantergan and is probably due to the release of
histamine. The best way to avoid this effect
in the clinical use of tubocurarine is to give
the injection slowly. Slow injections of large
doses in guinea -pigs had no effect on the bronchi,
although a dose ten to fifteen times smaller
caused bronchoconstriction when given rapidly.
