title: Differential toxicity of reactive metabolites of clindamycin and sulfonamides in HIV-infected cells: influence of HIV infection on clindamycin toxicity in vitro.
abstract: Hypersensitivity adverse drug reactions are much more common among patients with acquired immunodeficiency syndrome (AIDS) than in the general population. High rates of hypersensitivity reactions to clindamycin have been noted. To investigate the role of reactive metabolites in these reactions, the authors studied toxicity of clindamycin and sulphamethoxazole (SMX) and their metabolites in uninfected and human immunodeficiency virus (HIV)-infected MOLT3 cells. Infected and uninfected cells were incubated with clindamycin or sulphamethoxazole hydroxylamine in increasing concentrations; reactive metabolites were generated by coincubation of cells and drug with murine microsomes and a microsomal activating system. Over a concentration range of 0 to 400 microM SMX-HA, there was a significant concentration-dependent increase in cell death in HIV-infected compared to uninfected cells (28%+/-3% vs 8%+/-5% at 400 microM, P < .05). In contrast, coincubation of cells with clindamycin, microsomes, and a microsomal activating system, as well as combinations of primaquine or pyrimethamine, was not associated with an increase in cell death among infected compared to uninfected cells. No concentration-toxicity was demonstrated. These data support the role of reactive metabolites in adverse drug reactions to sulfonamides during HIV infection, whereas alternate mechanism(s) may be responsible for increased rates of adverse drug reactions to clindamycin among patients with AIDS.
authors.affiliation: John P. Robarts Research Institute, London, Ontario, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Wijsman
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dekaban
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rieder
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002981:Clindamycin / Q000378:metabolism / Q000633:toxicity*; D018920:Coculture Techniques; D004338:Drug Combinations; D004342:Drug Hypersensitivity / Q000209:etiology; D006678:HIV / Q000187:drug effects* / Q000472:pathogenicity; D051379:Mice; D008861:Microsomes; D011319:Primaquine / Q000633:toxicity; D011739:Pyrimethamine / Q000633:toxicity; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology
chemical_list: D000890:Anti-Infective Agents; D004338:Drug Combinations; C059873:sulfamethoxazole hydroxylamine; D002981:Clindamycin; D013420:Sulfamethoxazole; D011319:Primaquine; D011739:Pyrimethamine