Determination of the Acetylator Phenotype and Pharmacokinetics of Some Sulphonamides in Man

Abstract

The pharmacokinetics of sulphamethizole, sulphamethoxazole, sulphadiazine, sulphapyridine and sulphadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulphonamides is dependent on the urine flow. N4-Acetylsulphonamide concentration-time profiles for plasma and urine have been constructed for the sulphonamides. The percentage N4-acetylsulphonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulphadimidine is metabolically processes by 2 different isoenzymes, while sulphadiazine, sulphapyridine and sulphamethoxazole are processes by 1 acetylating isoenzyme. Sulphamethizole is acetylated to very little extent.

Bioconcentration and Elimination of Sulfamethazine and Its Main Metabolite in Sturgeon (Acipenser schrenkii)

“…Sulfamethazine is known to undergo metabolism to mainly form N 4 -acetyl-SM 2 in numerous species of domestic animals, including fish and humans (10)(11)(12)(13)(14). Metabolic alteration of the parent compound by fish to more polar species or to less polar species can have an impact upon bioconcentration (5), so N 4 -acetyl-SM 2 , which is less polar than SM 2 , was used as a biodegradation marker of the drug in the test organism.…”

Sulfadiazine Urolithiasis during Antitoxoplasma Therapy

“…Excretion rates of NASDZ higher than those of SDZ have been observed more frequently in a fast acetylator (Vree et al 1980). Since the aqueous solubility of NASDZ is greater than that ofSDZ at pH 5.0 (SDZ 103 mg/L, NASDZ 200 mg/L) [American Hospital Formulary Service 1991] and both compounds have reduced solubilities with decreasing pH, the most likely reason for the stones being mainly NASDZ was the high excretion rates of NASDZ (at least 3fold higher than that of SDZ in the one urine sample).…”

“…Reported Cmax values ofSDZ and NASDZ in serum/ plasma after a single 500mg dose of SDZ average about 20 mg/L (Bishop-Freudling & Vergin 1981; Springolo & Coppi 1989) and, depending on acetylator status, about 1 to 4 mg/L (Vree et al 1980), respectively. Reported Cmax values ofSDZ and NASDZ in serum/ plasma after a single 500mg dose of SDZ average about 20 mg/L (Bishop-Freudling & Vergin 1981; Springolo & Coppi 1989) and, depending on acetylator status, about 1 to 4 mg/L (Vree et al 1980), respectively.…”

“…Reported Cmax values ofSDZ and NASDZ in serum/ plasma after a single 500mg dose of SDZ average about 20 mg/L (Bishop-Freudling & Vergin 1981; Springolo & Coppi 1989) and, depending on acetylator status, about 1 to 4 mg/L (Vree et al 1980), respectively. Based on a terminal half-life of 12 hours (Vree et al 1980), the theoretical accumulation factor of a drug administered twice every half-life (dosing interval of 6 hours) is 3.4, assuming linear kinetics. During long term therapy, however, NASDZ probably accumulates to a greater extent than SDZ, because of its longer terminal half-life (NASDZ: 8-18 hours; SDZ: 7-12 hours) [Vree et al 1980], and therefore at some point in the terminal phase the serum levels of NASDZ may be greater than those of SDZ, such as observed in serum no.…”

“…Theoretically, increasing urinary pH and urine flow with forced hydration and oral sodium bicarbonate would have an effect on increasing SDZ excretion, decreasing NASDZ excretion, increasing the solubility of SDZ and NASDZ in urine (Vree et al 1980) and, thus, decreasing the likelihood of NASDZ stone formation. Theoretically, increasing urinary pH and urine flow with forced hydration and oral sodium bicarbonate would have an effect on increasing SDZ excretion, decreasing NASDZ excretion, increasing the solubility of SDZ and NASDZ in urine (Vree et al 1980) and, thus, decreasing the likelihood of NASDZ stone formation.…”