Biological availability of sulfamethoxypyridazine and sulfisomidine polymers.

Dissolution rates and apparent solubilities of forms I, II and III of Sulfamethoxypyridazine (1) and forms I and II of sulfisomidine (2) were determined in water at 37 degrees C. The ratios of apparent solubilities of I:II:III for 1 forms and I:II for 2 forms were 1:1.18:1.25 and 1:1.32 respectively. Upon long contact of 2 with water the ratio of II:I decreased. This has been attributed to gradual transformation of 2 from form II to I. Gastrointestinal absorption of form III of 1, in human volunteers, was studied in comparison with the more stable form I. The same study was carried out on forms I and II of 2. Data were correlated and expressed in availability rate constants (K1), applying the one compartment open: model. This and other parameters show that form III of 1 is 1.4 times as much absorbed as form I, and that the availability of the metastable form II of 2 is 1.2 times as much absorbed as the stable form I.

[Enteral absorption of sulfasomidine depending on age (author's transl)]. / Enterale Absorption von Sulfasomidin in Abhängigkeit vom Lebensalter.

After intravenous and oral application of 25 mg 6-(sulfanilamido)-2,4-dimethyl-pyrimidine (sulfasomidin)/kg body-weight to 29 newborns, 8 infants and 9 older children the completeness and rate of absorption were determined. Sulfasomidine was completely absorbed in newborns (mean value 95.7%) as well as in older children (mean value 94.4%). Concerning the rate of absorption there were age-dependent differences. Using the Bateman function for the kinetic model of intestinal absorption the rate constant of invasion k1 was significantly lower in the first week of life compared to that in older children. In agreement with these data the time tmax of the maximum serum concentration was significantly prolonged in newborns compared to that of older children.

Distribution of silfusomidine in tissues of poultry.

The biological half life, blood level and tissue dispersion of sulfisomidine in poultry have been studied. The biological half life was observed to be 40 minuts. Following single dose (275 mg/kg) oral administration, the peak blood level of 13.92 mg% was found at 2 hr and the liver and small intestine showed highest drug residue at the end of 24 hr.

Specifity and sensitivity of the inhibition of drug metabolism following inhalation of carbon disulphide-air mixtures.

A single 8-h exposure of adult female Wistar rats to 20 ppm carbon disulphide (CS2), the threshold limit value (TLV) in several countries, was sufficient to cause inhibition of the following drug-metabolizing reactions: formation of trichloroethanol and trichloroacetic acid from trichloroethylene (aliphatic C-hydroxylation), formation of 4-hydroxyantipyrine from antipyrine (quasi-aromatic C-hydroxylation), formation of acetaminophenol from acetanilid (aromatic C-hydroxylation) and phenacetin (oxidative odealkylation), respectively, and formation of 4-aminoantipyrine from aminopyrine (oxidative N-demethylation). The behaviour of these effects was dependent on the dose of CS2 administered in that the inhibitory process was enhanced when increasing the concentration to (50), 100, 200, and 400 ppm. The respective changes could be demonstrated by a short-duration (6-h) reduction in the urinary excretion of the metabolites. In the case of trichloroethylene the limitation in metabolite formation persisted for as long as 36 h due to the varying rate of formation of trichloroethanol and trichloroacetic acid. This deficiency in excretion was compensated in part during the subsequent elimination phase (up to 24 and 36 h, respectively), an observation which suggests the rapid reversibility of the alteration. As shown by the respective prolongation of the hexobarbital sleeping time in the rat, the side-chain oxidation of hexobarbital to ketohexobarbital was increasingly inhibited by rising concentrations of CS2 in the range of 20 to 400 ppm/8 h. On the basis of the present results it is concluded that CS2 also inhibits various oxygenases of the microsomal enzyme system. In adult female NMRI mice a significant inhibition of the microsomal procaine-hydrolyzing esterase of the liver was observed only after 400 ppm/8 h; however, this limitation did not affect the LD50 of procaine-HCl, particularly as the corresponding serum esterase activity also remained uninfluenced. The aromatic N-acetylation of sulphisomidine and the quasi-aromatic N-acetylation of 4-aminoantipyrine in rats failed to be significantly reduced by CS2 even after 400 ppm/8 h, nor did the same dose of CS2 affect the glucuronidation of 4-hydroxyantipyrine in the same animal species. It is concluded from the above results that the specificity and sensitivity of the inhibition of drug metabolism observed in small laboratory animals is probably similar to that prevailing in man. This assumption has already been substantiated for the oxidative N-demethylation of aminopyrine.

[The geriatric pharmacology of cefazolin, cefradin and sulfisomidine]. / Die geriatrische Pharmakologie von Cefazolin, Cefradin und Sulfisomidin

Clinical pharmacology of 3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-8-oxo-7-(tetrazol-1-ylacetamido)-5-thia-1-azabicyclo-(4,2,0)oct-2-en-carbonic acid (cefazolin) and D-7-[2-amino-(cyclohexa-1,4-dien-1-yl)-acetamido]-3-methyl-8-oxo-5-thia-1-aza-(4,2,0)-oct-2-ene-2-carbonic acid monohydrate (cefradine) was compared in young and old adults without renal disease after i.v. injection of 1 g. Mean serum levels of cefazolin after 4 h and 6 h were significantly higher in old persons (25.0 and 14.7 mug/ml, resp.) than in young persons (16.2 and 7.8 mug/ml, resp.). Serum concentrations of cefradine after 2 and 4 h were found also higher in the aged (11.2 and 4.4 mug/ml, resp.) than in young adults. Half-life of cefazolin was prolonged from normally 94 min to 189 min, half-life of cefradine from 32 min to 72 min. Skin blister fluid punctured once for antibiotic assay contained less cefazolin in old persons (after 4 and 6 h only 22.4 and 17.4 mug/ml, resp.) than in young persons (32.7 and 27.6 mug/ml, resp.). Cefradine levels in skin blister fluid 0.5 and 1 h after i.v. injection showed also a significant difference (11.4 and 11.9 mug/ml, resp.) in old persons, 17.3 and 16.5 mug/ml, resp., in young persons). Elimination constants (alpha, beta, kel, k12, k21) were always lower in geriatric patients. Renal clearance of cefazolin was reduced from 83 ml/min to 43 ml/min, and renal clearance of cefradine from 378 ml/min to 152 ml/min. After i.v. injection of 1 g 6-sulfanilamido-2,4-dimethyl-pyrimidine (sulfisomidine) total content of the drug in blood was higher in elderly people than in young persons, but proportion of acetylated sulfisomidine was nearly the same in both groups (15%). It is supposed that higher serum levels of some drugs in old persons (over 70 years) can be explained by impaired renal excretion and slower tissue penetration of the compound from the blood.