Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the dissociation of the drug.

We aimed to clarify the relationship between drug dissociation (sulphisomidine) and its direct transport from the nasal cavity to the cerebrospinal fluid (CSF). Rat nasal cavities were perfused in a single pass system with buffers (pH 5.5, 6.5, 7.4, 8.7 and 9.4). Plasma and CSF were collected and the concentration of sulphisomidine was measured. Nasal clearance increased with the increase in the un-ionized fraction of the drug. The ratio of the drug concentration in CSF to that in the nasal perfusion fluid (the index of the degree of the drug transport from the nasal cavity to CSF), was changed in accordance with the un-ionized fraction of drug. These results show that both the nasal absorption and the drug transport conform to the pH partition theory.

Renal tubular excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine in the dog.

To investigate whether dogs are able to excrete acetylated drugs by active transport, the plasma kinetics and renal excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine were studied in the beagle dog after a rapid intravenous bolus injection. Two doses of N4-acetylsulphasomidine (1050 and 105 mg) and one dose of N4-acetylsulphadimethoxine (472 mg) were administered on separate occasions. The renal clearance (CLR) was as follows: N4-acetylsulphasomidine (1050 mg) 34 mL min-1; N4-acetylsulphasomidine (105 mg) 28 mL min-1; and N4-acetylsulphadimethoxine (472 mg) 24 mL min-1. CLR was higher than expected on the basis of the measured glomerular filtration rate, indicating that the N4-acetyl metabolites may be excreted by the renal tubules by active tubular transport. Saturation of the excretion process of N4-acetylsulphasomidine occurred with a transport maximum of 930 +/- 190 micrograms min-1 and a Michaelis-Menten constant of 37 +/- 10 micrograms mL-1. It may be concluded that the dog renal organic anion transport system is able to secrete acetylated sulphonamides.

Therapeutic equivalence of sulfaisodimidine 2 g twice daily and 1 g four times daily in lower urinary tract infections.

The serum concentrations and clinical effects of sulfaisodimidine given during 12 days were examined in two groups of patients with uncomplicated lower urinary tract infection. Group I (n=12) received the drug in a conventional dosage, 1 g four times daily, and group II (n=14) in a dose of 2 g twice daily. The serum concentrations of sulfonamide at steady state (day 7) and one day after cessation of therapy (day 13) did not differ significantly between the groups. With the exception of one patient in group I, both subjective and objective symptoms vanished during treatment and remained absent for at least 4 weeks thereafter. Two patients in each group developed signs of sulfonamide allergy. Thus, the two regimens seemed to be equally efficient, and the risk of therapy failure due to low blood concentrations of sulfaisodimidine should not be greater when the drug is given in a dosage of 2 g twice daily than when it is administered in the conventional way. Hence, the latter, simpler regimen can be recommended.

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.

On the influence of concomitant food intake on sulfonamide bioavailability.

The influence of food intake on the bioavailability of a frequently used short-acting sulfonamide, sulfaisomidine (Elkosin), has been examined in eight healthy volunteers. The drug was administered as a single oral dose, both on an empty stomach and together with a standardized breakfast. Numerous venous blood samples were drawn for the first eight hours after ingestion of the drug, and the concentration of unmetabolized sulfonamide in serum was assessed by spectrophotometry. The observations indicate that concomitant food intake alters neither absorption rate, peak concentration, time to reach peak concentration, elimination rate, nor total amount of sulfonamide reaching the general circulation. Thus, the absorption of orally administered sulfaisodimidine is not at all affected by concomitant intake of food. This finding contrasts with previous observations on some other sulfonamides, and it may signify a therapeutic advantage of sulfaisodimidine. In addition, the amount absorbed showed only a little interindividual variation. This suggests that the use of standardized size and interval of sulfaisodimidine dosage can be recommended. The present findings emphasize that conclusions about the absorption of a certain drug should not be derived from studies with other, albeit chemically related, compounds.