Abstract
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)
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|