Kinetic phenotypic diagnosis of N-acetylation polymorphism in patients based on ratio of urinary metabolites of salicylazosulfapyridine.
We found that N-acetylation polymorphism can be evaluated from the disposition kinetics of sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) and their acetylated metabolites generated by N-acetyltransferase (NAT2) after oral administration of salicylazosulfapyridine (SASP). In 126 Japanese subjects, the homozygote of NAT2*4 was the most frequent (40%), followed by heterozygotes of NAT2*4 and mutant genes (28% NAT2*4/*6A, 15% NAT2*4/*7B, and 2% NAT2*4/*5B). Combinations of mutant genes accounted for 16%. When the relationship between the molar ratio of N-acetyl-SP (Ac-SP)/SP or N-acetyl-5-ASA(Ac-5-ASA)/5-ASA in serum and five genotypes of polymorphic NAT2* was examined in patients who received multiple doses of SASP, the molar ratios of Ac-SP/SP, rather than Ac-5-ASA/5-ASA tended to decrease according to the classification of genotype. We calculated the pharmacokinetic parameters in healthy subjects with various genotypes of polymorphic NAT2* after a single p.o. administration of SASP, according to a model of the SP metabolic pathways. The molar ratios of Ac-SP/SP in serum and urine were simulated using these parameters, and the molar ratio of Ac-SP/SP in urine at 4 days after the first administration could be categorized into ranges that were specific to various NAT2* genotypes. Thus, we were able to predict the N-acetylation polymorphic genotypes of patients by measuring the molar ratio of Ac-SP/SP in urine, after administration of SASP.
Yokogawa
K
K
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1, Takara-machi, 920-8641, Kanazawa, Japan.
Nakaharu
T
T
Ishizaki
J
J
Ozaki
E
E
Takeda
Y
Y
Mabuchi
H
H
Matsushita
R
R
Kimura
K
K
Nakashima
E
E
Ichimura
F
F
Miyamoto
K
K
D000107:Acetylation; D000328:Adult; D000636:Aminosalicylic Acids / Q000493:pharmacokinetics; D001711:Biotransformation; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D013427:Sulfapyridine / Q000493:pharmacokinetics; D012460:Sulfasalazine / Q000493:pharmacokinetics / Q000652:urine*; D014376:Tuberculosis / Q000378:metabolism
D000636:Aminosalicylic Acids; D012460:Sulfasalazine; D004247:DNA; D013427:Sulfapyridine