Inhibition of dapsone-induced methaemoglobinaemia by cimetidine in the presence of trimethoprim in the rat.
Administration of dapsone in combination with trimethoprim and cimetidine to male rats resulted in a marked decrease (P less than 0.05) in measured methaemoglobin levels (46.2 +/- 24% Met Hb h) compared with administration of dapsone alone (124.5 +/- 24.4% Met Hb h). The elimination half-life of dapsone (814 +/- 351 min) was more than doubled in the presence of trimethoprim and cimetidine compared with control (355 +/- 160 min, P less than 0.05). However, there were no significant differences in AUC and clearance when dapsone was administered in combination with trimethoprim and cimetidine compared with dapsone alone. Co-administration of trimethoprim with dapsone in the absence of cimetidine did not affect either methaemoglobin formation, AUCs, half-lives, or clearance values of dapsone compared with control. There was a threefold increase in the AUC of trimethoprim (6296 +/- 2249 micrograms min mL-1) in the presence of dapsone compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1). There was also a corresponding decrease in the clearance of trimethoprim in the presence of dapsone compared with control (19.1 +/- 6.9 vs 60.8 +/- 21.0 mL min-1). However, there was no change in the elimination half-life of trimethoprim between the two experimental groups (273 +/- 120 vs 292 +/- 54 min). The AUC of trimethoprim increased more than threefold in the presence of cimetidine (7100 +/- 1501 micrograms min mL-1) compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Coleman
M D
MD
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Russell
R M
RM
Tingle
M D
MD
Park
B K
BK
D000107:Acetylation; D000818:Animals; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology*; D003622:Dapsone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D006207:Half-Life; D008297:Male; D008706:Methemoglobin / Q000032:analysis; D008708:Methemoglobinemia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014295:Trimethoprim / Q000008:administration & dosage / Q000494:pharmacology*
D002927:Cimetidine; D003622:Dapsone; D008706:Methemoglobin; D014295:Trimethoprim