Role of pharmacokinetics and metabolism in the enhanced susceptibility of middle-aged male Sprague-Dawley rats to acetaminophen nephrotoxicity.
Middle-aged male Sprague-Dawley (SD) rats (9-12 months) are more susceptible to acetaminophen (APAP)-induced nephrotoxicity than are young (2-3 months) adult males. The present studies were designed to evaluate the role of pharmacokinetics and renal and hepatic metabolism of APAP in age-dependent nephrotoxicity. Following 750 mg/kg APAP, ip, a nephrotoxic dosage in 12-month-old but not 3-month-old rats, renal cortical APAP concentrations were significantly greater in 12-month-old compared with 3-month-old SD rats at 3, 4, and 6 hr after treatment. Renal medullary APAP concentrations in 12 month-old rats were significantly greater than in 3-month-old rats at 2, 3, and 5 hr after treatment. Serum APAP concentrations were significantly elevated in 12-month-old compared with 3-month-old rats from 2 through 5 hr after APAP (750 mg/kg ip). However, APAP tissue/serum concentration ratios were similar in 3- and 12-month-old rats, indicating that differences in tissue concentration were secondary to increased serum concentrations in older rats. Conjugated APAP metabolites in blood were similar in 3- and 12-month-olds during the initial 2-3 hr after 750 mg/kg APAP, ip, but began to accumulate in 12-month-old but not 3-month-old rats within 6-8 hr after APAP administration, perhaps secondary to declining renal function. After 500 mg/kg APAP, iv, blood APAP concentrations were markedly elevated in 12-month-old compared with 3-month-old rats during the entire course of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)
Tarloff
J B
JB
Department of Investigative Toxicology, Smith Kline & French Laboratories, King of Prussia, PA 19406-0939.
Goldstein
R S
RS
Mico
B A
BA
Hook
J B
JB
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000367:Age Factors; D000818:Animals; D005965:Glucuronates / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D005965:Glucuronates; D000082:Acetaminophen