Coleman MD, Kohl C; International Conference on AIDS.
Int Conf AIDS. 1996 Jul 7-12; 11: 89 (abstract no. Mo.B.1204).
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK. Fax: 44 121 359 0733. E-mail: m.d.coleman@aston.ac.uk.
Objectives: to determine if sulphametrole (SMT) is less toxic in vitro compared with sulphamethoxazole (SMX). Methods: three toxicity tests have been used, all of which depended on rat liver microsomes (with or without the necessary NADPH for oxidative metabolism) to generate cytotoxic metabolites of SMX and SMT. They were test 1 (microsomes, human mononuclear leucocytes and either SMX or SMT; trypan blue exclusion indicates toxicity), test 2 (microsomes, human erythrocytes, drugs; methaemoglobin generation indicates toxicity) and test 3 (microsomes, erythrocytes and drugs, separated by a cellulose membrane in a two-compartment model; methaemoglobin indicates toxicity). Drug vehicle (methanol) concentration less than 1% of incubation vol.). Statistical analysis was by Student's t' test (with Bonferroni correction); data expressed as mean plus or minus SD, n=4. approximately ,*,+ denote P less than 0.05, 0.01 and 0.001. Results: (table: see text) Background toxicity for test 1 (microsomes, vehicle, cells; 9.3 plus or minus 3.4%)) was not significantly different from NADPH free test 1 incubations. Neither compound was toxic in the absence of NADPH. In all three tests with NADPH, toxicity was significantly lower with SMT compared with SMX. In test 1, SMT showed no significant toxicity. Both compounds were significantly less toxic in test 3 compared with test 2, indicating that their metabolites were insufficiently stable to retain toxicity when traversing distance and membranes. Conclusions: although as with SMX, SMT is probably activated to a hydroxylamine in vitro, SMT is significantly less toxic compared with SMX. This may be due to reduced activation of SMT to the hydroxylamine and instability of the toxic species. Future clinical trials will determine if this difference shown in vitro occurs in vivo.
Publication Types:
Keywords:
- Animals
- Erythrocytes
- Humans
- In Vitro
- Leukocytes, Mononuclear
- Methemoglobin
- Microsomes, Liver
- NADP
- Rats
- Sulfamethoxazole
- toxicity
Other ID:
UI: 102217167
From Meeting Abstracts