Chronic effects of fractionated renal irradiation on the pharmacokinetics of intravenous methotrexate.
the chronic effects of renal irradiation on the pharmacology of methotrexate was studied in a rat model. Unanesthetized rats received 2 doses of bilateral fractionated kidney irradiation (16.2 Gy or 19.8 Gy in 9 fractions). Alterations in renal function were first seen at 3 months in the 19.8 Gy group and 12 months in the 16.2 Gy groups. Life table analysis showed a shift in the survival curve of about 3 months between the 2 radiation doses. The pharmacokinetics of i.v. methotrexate showed an increase in the area under the plasma curve beginning at 9 months in the 19.8 Gy group and at 15 months in the 16.2 Gy group. The volume of distribution of methotrexate was smaller in the irradiated rats than in unirradiated controls. Multiple linear regression models showed significant correlations between parameters of methotrexate clearance and certain renal function tests. Nevertheless, no set of renal function tests consistently predicted alteration in methotrexate clearance in the 2 radiation groups. Furthermore, time after irradiation remained a highly significant variable indicating that renal irradiation causes time dependent change in methotrexate pharmacokinetics that can not be accounted for by the usual tests of renal function.
D000818:Animals; D003404:Creatinine / Q000652:urine; D005260:Female; D007668:Kidney / Q000378:metabolism / Q000528:radiation effects*; D007700:Kinetics; D008727:Methotrexate / Q000097:blood / Q000378:metabolism* / Q000652:urine; D009393:Nephritis / Q000378:metabolism; D011507:Proteinuria / Q000652:urine; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000378:metabolism; D051381:Rats
D003404:Creatinine; D008727:Methotrexate