Crystalline sulphormcthoxine on single oral administration to mice was no more toxic than sulphadimethoxine and sulphamethoxydiazine and considerably less toxic than sulphamethoxypyridazine. Orally, the microcrystalline form was slightly more toxic than the crystalline form and about twice as toxic when given subcutaneously or intraperitoneally. Injection of the 25 Vo ampoule solution in rats and rabbits intravenously, intracutaneously and intramuscularly caused only mild to moderate local irritation. In five to six weeks toxicity tests, rats tolerated 250 mg/kg, rabbits 1000 mg/kg and dogs 100 mg/kg/day without harmful effects. In tests of longer duration, rats tolerated 120 mg/kg/day for 18 months, dogs 50 mg/kg/day for six months and 200 mg/kg/week for four months, without harmful effects except for the well-known thyroid hyperplasia svhich usually occurs when high doses of sul-phonamides are given for prolonged periods. Much higher doses caused bone marrow depression in a few growing rats, and in dogs some haemolysis, and opacity of the ocular lenses occurred. Monkeys have completed a trial lasting 54 weeks when doses of 100 mg/kg/week and of 50 mg/kg/day were given, without harmful effects. Special studies to discover any teratogenic effects in mice, rats and rabbits with daily doses occasionally 10-13 times higher than the weekly doses recommended for man, did not cause any anomalies in the offspring. In disc tests, sulphormethoxine inhibited several strains of staphylococci, streptococci, pneuniococci, meningococci, E. coli, Shigella, Klebsiella and H. influenzae Type B. Proteus and strains of S. typhimurium were less sensitive. Enterococci, Pscudomonas and H. injluenzae Type A were also unaffected by sulphormethoxine. The smaller zones of inhibition produced by the sulphormethoxine discs are associated with its lesser diffusion in the medium. By comparative studies of sulphormethoxine and four other sulphonamides in animals against pathogenic bacteria, fungi and plasmodia, we were able to distinguish the particularly broad spectrum of sulphormethoxine. Sulphormethoxine is effective against staphylococci, streptococci, pneumococci, E. coli, Proteus, Klebsiella, Salmonella, Histoplasma capsulatum and malaria parasites. Due to its long half-life, single doses of sulphormethoxine confer prolonged protection in mice infected with E. coli compared with the protection offered by single doses of sulphadiazine. Sulphormethoxinc has also been shown to be active against M. leprae. In man a single oral dose of sulphormethoxine produces plasma levels similar to those obtained following intravenous or intramuscular injections. Maximum values are usually reached after 4 h. By the rectal route absorption is approximately two-thirds that following other routes. Sulphormethoxine can be distinguished from other sulphonamides by its very slow elimination from plasma. Its half-life averages 179 h whilst that of sutphadiniethoxine is 35 h, of sulphamethoxydiazine 37 h and of sulphadiazine 17 h. Thus effective therapeutic levels in the plasma can be maintained by weekly doses of sulphormethoxine. In human plasma, from 5-17% of the total sulphormethoxine is acetylated at the N4-position, and 2-3 % is bound to glucuronic acid. The remainder, consisting of chemically unchanged substance, is mostly bound to plasma proteins. In persons with uninflamed meninges, the level of non-acetylated, free sulphormethoxine in the CSF is between one-eighth and one-fifth of the simultaneous plasma levels. In patients with meningococcal meningitis, single intramuscular injections produce levels in the CSF corresponding to between a quarter and a third of the simultaneous plasma levels. In synovial, pleural and ascitic fluids the concentration of free sulphonamide varied from approximately one-third to one-half of simultaneous plasma levels and in the tissues concentrations varied from approximately one-fifteenth to two-fifths of simultaneous plasma levels when these were around 15 mg%. Samples of bile obtained during cholecystectomies approximately four days after injection of 2 g sulphormethoxine, had levels of sul-phormethoxine approximately one-quarter to one-third of simultaneous plasma levels. The proportion of metabolisedsul phonamide was considerably greater in the bile than in the plasma, but the amount of active sulphonamide was not less than that in the plasma. After an oral dose of 2 g sulphormethoxinc, 0.6-2.9 mg% free sulphonamide was found in maternal milk 48 h later. The level in the milk dropped approximately two and a half times more rapidly than the plasma level. In the cord blood of new-born infants, after a single oral dose of 1 g sulphormethoxine had been given to the mothers before delivery, the level of free sulphonamide was approximately three-quarters of that in the maternal plasma. Excretion studies with 35S-labelled sulphormethoxine showed that approximately 90°/o was excreted in the urine and 10% in the faeces. Further studies showed that with sulphormethoxine approximately two-thirds of that appearing in the urine is in the acetylated form and one-third as non-acetylated sulphonamide and about 37 °/β of the latter is present as the glucuronide. On regular weekly administration urinary excretion remains fairly constant suggesting that an equilibrium develops between administration and renal excretion. The urinary content of unchanged, unbound and thus active sulphormethoxine is at least as high as that of the simultaneous amount in the plasma. The maximum solubility of unchanged sulphormethoxine in human urine at 37° С and pH 5.0 is 21 mg%, and of the acetyl derivative 23 mg%. The solubilities increase rapidly with increasing pH values. Crystalluria has never yet been reported in patients treated with sulphormethoxine. Glomerular filtration of sulphormethoxine is relatively slow and the rate of tubular reabsorption for the free sulphonamide lies between 91 and 98%, for the glucuronide between 70 and 89% and for the acetylated portion is approximately 88%. The high rate of tubular reabsorption probably explains the long half-life of sulphormethoxine. © 1969 S. Karger AG, Basel.
