Inhibition of 7-hydroxymethotrexate formation by amsacrine.
The inhibition of methotrexate (MTX) biotransformation to 7-hydroxymethotrexate (7-OH-MTX) by 4'-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA) was studied in bile-drained rats in vivo and in incubates of isolated rat hepatocytes and rat-liver homogenate in vitro. In vivo, i.v. administration of 10 mg/kg mAMSA prior to [3H]-MTX infusion (50 mg/kg) led to a significant alteration in 7-OH-MTX kinetics. 7-OH-MTX peak concentrations and AUC in bile and serum were reduced by 75% and the recovery of MTX as 7-OH-MTX in bile and urine decreased by 70%, whereas MTX pharmacokinetics remained unaltered. In suspensions of isolated hepatocytes, 10 microM mAMSA led to a 54% decrease in 7-OH-MTX formation. However, the hepatocellular influx and efflux of MTX was not perturbed by mAMSA. Preincubation of rat-liver homogenates with 1.25-10 microM mAMSA reduced the formation of 7-OH-MTX by up to 73%. mAMSA appeared to inhibit MTX hydroxylation competitively, exhibiting a Ki of 3 microM. Due to its inhibition of the MTX-oxidizing system, mAMSA may be beneficial in combination chemotherapy with MTX by reducing 7-OH-MTX-associated toxicity and, possibly, enhancing the cytotoxic effects of MTX.
Department of Pharmacology, University of Tromsø, Norway.
R M
RM
Bremnes
E
E
Smeland
N P
NP
Willassen
E
E
Wist
J
J
Aarbakke
D000677:Amsacrine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured / Q000737:chemistry / Q000378:metabolism; D006900:Hydroxylation; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000677:Amsacrine; C011864:7-hydroxymethotrexate; D008727:Methotrexate