The metabolism of 4-aminobiphenyl in rat. I. Reaction of N-hydroxy-4-aminobiphenyl with rat blood in vivo

Abstract

1. ³H-4-Aminobiphenyl (ABP, 5 mg) given i.p. to rat had elimination half-lives of 15.6, 17 and 17 h, respectively, for urinary, faecal and total ³H elimination. ¹⁴C-ABP administered orally to rats at 100 mg/kg gave elimination half-lives of 31, 36.7 and 34 h, respectively, for urinary, faecal and total ¹⁴C elimination.

2. Semi-log plots of percentage dose remaining in the body versus time indicated that: (i) 82% of ³H activity was excreted in 36 h with a half-life of 14.4 h and 18% with a half-life of 46.2 h, and (ii) 77% of ¹⁴C activity was excreted in 48 h with a half-life of 15 h and 23% with a half-life of 180 h.

3. After i.p. injection of 10 mg/kg ¹⁴C-ABP to rats, ferrihaemoglobin (HbFe³⁺) concn increased to 60% in 2h, accompanied by accumulation of ¹⁴C activity in erythrocytes, indicating that the active metabolite, N-hydroxy-4-aminobiphenyl (N-hydroxy-ABP) had oxidized haemoglobin-Fe²⁺ (HbFe²⁺) and was bound to the erythrocyte.

4. ABP given i.p. to rats at 0.24 mmol/kg rapidly appeared in blood, disappeared with a half-life of 30 min, and blood concn plateaued at 30 nmol/ml. The concn of 4-acetyl-aminobiphenyl (AABP) plateaued at 17 nmol/ml after 15 min, indicating a dynamic equilibrium between N-acetylation of ABP and N-deacetylation of AABP. The concn of 4′-hydroxy-4-acetylaminobiphenyl (4′-hydroxy-AABP) increased slowly at 1.65 nmol/h.

5. AABP given i.p. to rats at 0.88 mmol/kg slowly appeared in the blood, accompanied by the appearance of ABP and 4′-hydroxy-AABP and formation of HbFe³⁺. After 4 h the concn of AABP and ABP was 27.35 mmol/ml, indicating a dynamic equilibrium between N-deacetylation of AABP and acetylation of ABP. Neither N-hydroxy-ABP nor N-hydroxy-4-acetylaminobiphenyl (N-hydroxy-AABP) were found.