Thiocolchicoside

Thiocolchicoside is a semisynthetic sulphide derivative of colchicoside, showing muscle relaxant pharmacological activity.

In vitro thiocolchicoside binds solely with gaba receptors and glycinergic stricnine sensitive. From the moment that thiocolchicoside acts as an antagonist of the gaba receptors, its muscle relaxant effect may be exercised to a supraspinal level, through a regulatory mechanism even though the glycinergic mechanism of action cannot be excluded. The characteristics of interaction with the gaba receptors are qualitative and quantitative divided between thiocolchicoside and its main circulating metabolite, the derivative glucuronidated.

In vivo the muscle relaxant properties of thiocolchicoside and its main metabolite have been shown in various predictive models of rat and rabbit.

The lack of muscle relaxant effect of thiocolchicoside in spineless rat suggests a predominant supraspinal activity.

Also electrocephalographic studies have shown that thiocolchicoside and its main metabolite are devoid of any sedative effect.

Absorption

After IM administration, thiocolchicoside C_max occur in 30 min and reach values of 113 ng/mL after a 4 mg dose and 175 ng/mL after a 8 mg dose. The corresponding values of AUC are respectively 283 and 417 ng.h/mL. The pharmacologically active metabolite SL18.0740 is also observed at lower concentrations with a C_max of 11.7 ng/mL occurring 5 h post dose and an AUC of 83 ng.h/mL. No data are available for the inactive metabolite SL59.0955.22

After oral administration, no thiocolchicoside is detected in plasma. Only two metabolites are observed: The pharmacologically active metabolite SL18.0740 and an inactive metabolite SL59.0955. For both metabolites, maximum plasma concentrations occur 1hour after thiocolchicoside administration. After a single oral dose of 8 mg of thiocolchicoside the C_max and AUC of SL18.0740 are about 60 ng/mL and 130 ng.h/mL respectively. For SL59.0955 these values are much lower: C_max around 13 ng/mL and AUC ranging from 15.5 ng.h/mL (until 3h) to 39.7 ng.h/mL (until 24h).

Distribution

The apparent volume of distribution of thiocolchicoside is estimated around 42.7 L after an IM administration of 8 mg. No data are available for both metabolites. Biotransformation After oral administration, thiocolchicoside is first metabolized in the aglycon 3-demethyltiocolchicine or SL59.0955. This step mainly occurs by intestinal metabolism explaining the lack of circulating unchanged thiocolchicoside by this route of administration. SL59.0955 is then glucuroconjugated into SL18.0740 which has equipotent pharmacological activity to thiocolchicoside and thus supports the pharmacological activity after oral administration of thiocolchicoside. SL59.0955 is also demethylated into didemethyl-thiocolchicine.

Elimination

After IM administration the apparent t_1/2 of thiocolchicoside is 1.5h and the plasma clearance 19.2 L/h.

After oral administration, total radioactivity is mainly excreted in feces (79%) while urinary excretion represents only 20%. No unchanged thiocolchicoside is excreted either in urine or feces. SL18.0740 and SL59.0955 are found in urine and feces while the didemethyl-thiocolchicine is only recovered in feces. After oral administration of thiocolchicoside, the SL18.0740 metabolite is eliminated with an apparent t_1/2 ranging from 3.2 to 7 hours and the metabolite SL59.0955 has a t_½ averaging 0.8h.

Thiocolchicoside profile has been assessed in vitro, and in vivo following parenteral and oral administration.

Thiocolchicoside was well tolerated following oral administration for periods of up to 6 months in both the rat and the non-human primate when administered at repeated doses of less than or equal to 2 mg/kg/day in the rat and less or equal to 2.5 mg/kg/day in non-human primate, and by the intramuscular route in the primate at repeated doses up to 0.5 mg/kg/day for 4 weeks.

At high doses, thiocolchicoside induced emesis in dog, diarrhoea in rat and convulsions in both rodents and nonrodents after acute administration by oral route.

After repeated administration, thiocolchicoside induced gastro-intestinal disorders (enteritis, emesis) by oral route and emesis by IM route.

Thiocolchicoside itself did not induce gene mutation in bacteria (Ames test), in vitro chromosomal damage (chromosome aberration test in human lymphocytes) and in vivo chromosomal damage (in vivo micronucleus in mouse bone marrow administered intraperitoneally).

The major glucuro-conjugated metabolite SL18.0740 did not induce gene mutation in bacteria (Ames test); however it induced in vitro chromosomal damage (in vitro micronucleus test on human lymphocytes) and in vivo chromosomal damage (in vivo micronucleus test in mouse bone marrow administered orally). The micronuclei predominantly resulted from chromosome loss (centromere positive micronuclei after FISH centromere staining), suggesting aneugenic properties. The aneugenic effect of SL18.0740 was observed at concentrations in the in vitro test and at AUC plasma exposures in the in vivo test higher (more than 10 fold based on AUC) than those observed in human plasma at therapeutic doses.

The aglycon metabolite (3-demethylthiocolchicine-SL59.0955) formed mainly after oral administration induced in vitro chromosomal damage (in vitro micronucleus test on human lymphocytes) and in vivo chromosomal damage (in vivo oral micronucleus test in rat bone marrow administred orally). The micronuclei predominantly resulted from chromosome loss (centromere positive micronuclei after FISH or CREST centromere staining), suggesting aneugenic properties. The aneugenic effect of SL59.0955 was observed at concentrations in the in vitro test and at exposures in the in vivo test close to those observed in human plasma at therapeutic doses of 8 mg twice daily per os. Aneugenic effect in dividing cells may result in aneuploid cells. Aneuploidy is a modification in the number of chromosomes and loss of heterozygosity, which is recognized as a risk factor for teratogenicity, embryotoxicity/spontaneous abortion, impaired male fertility, when impacting germ cells and a potential risk factor for cancer when impacting somatic cells. The presence of the aglycon metabolite (3-23 demethylthiocolchicine-SL59.0955) after intramuscular administration has never been assessed, therefore its formation using this route of administration cannot be excluded.

In the rat, an oral dose of 12 mg/kg/day of thiocolchicoside caused major malformations along with foetotoxicity (retarded growth, embryo death, impairment of sex distribution rate). The dose without toxic effect was 3 mg/kg/day.

In the rabbit, thiocolchicoside showed maternotoxicity starting from 24 mg/kg/day. Furthermore, minor abnormalities have been observed (supernumerary ribs, retarded ossification).

In a fertility study performed in rats, no impairment of fertility was seen at doses up to 12 mg/kg/day, i.e. at dose levels inducing no clinical effect. Thiocolchicoside and its metabolites exert aneugenic activity at different concentration levels, which is recognised as a risk factor for impairment of human fertility.

The carcinogenic potential was not evaluated.