Alterations in the cardiopulmonary effects and pharmacokinetics of a bisphosphonate drug by a cytochrome P-450 inhibitor in conscious rats.
U-91502, a bisphosphonate for arthritic inflammation treatment, was evaluated for its parental toxicity. The objective was to differentiate between the parent drug and a reactive metabolite(s) as the proximate cause of the toxic effects using two methods. The first method was to block the metabolism of U-91502 with a broad-spectrum cytochrome P-450 inhibitor, 1-aminobenzotriazole (ABT), to increase its toxicity. The second method was to scavenge any electrophilic intermediates of U-91502 with supplemental nucleophiles, L-methionine (LM) and N-acetylcysteine (NaLc) to decrease its toxicity. Two groups of rats each were given an i.v. injection of saline or ABT followed by an i.v. infusion of U-91502 at a constant dose rate. A third group was given two oral doses of LM followed by a co-infusion of U-91502 and NaLc. The breathing rate (BR) and electrocardiogram (ECG) of the rats were monitored. Blood samples were taken at specified time points for plasma drug concentration analyses (PDC) and pharmacokinetics determination. Each rat was infused until its BR was depressed by approximately 30% from the rates prior to injection of saline or ABT, or the second oral dose of LM. Thereafter, half of the rats in each group were sacrificed immediately and the remaining half at 180 min post infusion. All infused rats, except for those of the co-infusion group, and a group of untreated rats were analyzed for hepatic non-protein sulfhydryl for indication of glutathione depletion. The results indicated that ABT pretreatment expedited the elevation of PDC to a critical level that caused BR and then heart rate (HR) depression and ECG alterations. There was no unusual depletion of glutathione. The maximum concentration and the area under the curve were significantly increased while the total clearance was significantly reduced. Consequently, the postinfusion PDC remained high and the BR and HR depressions persisted. LM and NaLc did not alleviate the toxicity or alter the pharmacokinetics of U-91502. It was concluded that the toxic effects of U-91502 were due mainly to the parent drug and not the metabolites.
Leong
B K
BK
Investigative Toxicology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
Sabaitis
C P
CP
Rop
D A
DA
Jeffrey
P
P
Parker
T J
TJ
Burton
N K
NK
Petry
T W
TW
Jolly
R A
RA
Cooper
M M
MM
D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004562:Electrocardiography / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D009943:Organophosphorus Compounds; D014230:Triazoles; C102343:U 91502; C033020:1-aminobenzotriazole; D003577:Cytochrome P-450 Enzyme System; D008715:Methionine; D005978:Glutathione; D000111:Acetylcysteine