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PubMedDate not supplied

Effect of microsomal enzyme inducers on biliary and urinary excretion of acetaminophen metabolites in rats. Decreased hepatobiliary and increased hepatovascular transport of acetaminophen-glucuronide after microsomal enzyme induction.

Treatment of rats with phenobarbital (PB), 3-methylcholanthrene, and pregnenolone-16 alpha-carbonitrile increased the total (biliary plus urinary) excretion of thioether and glucuronic acid conjugates of acetaminophen (AA) without influencing AA-sulfate excretion, suggesting that these microsomal enzyme inducers enhance both cytochrome P-450-mediated toxication and UDP-glucuronosyltransferase-mediated detoxication of AA. However, induction with transstilbene oxide (TSO) did not increase the total excretion of AA-thioethers or AA-glucuronide and decreased AA-sulfate excretion. In addition, all inducers increased the ratio of AA metabolites excreted into urine over that excreted into bile. The extent of this shift from biliary to urinary excretion was dependent on both the AA metabolite and the inducer. The largest shift in the excretory route was seen with AA-glucuronide and induction with PB and TSO as inducers. Specifically, PB and TSO treatments decreased biliary excretion of AA-glucuronide by 70 and 89%, respectively, and increased its blood concentration up to 6- and 11-fold and urinary excretion 3- and 3.6-fold, respectively. Galactosamine depletes UDP-glucuronic acid from the liver only, thereby inhibiting hepatic but not extrahepatic glucuronidation. Galactosamine treatment prevented the PB-induced increase in AA-glucuronide in blood and urine. This suggests that the PB-induced increases in AA-glucuronide in blood and urine originated from the liver. Thus, microsomal enzyme inducers not only influence xenobiotic biotransformation, but may also after the contribution of the excretory routes (i.e. bile and urine) in the elimination of xenobiotic metabolites by changing the direction of hepatic transport.

Acetaminophen↗

PubMedDate not supplied

Effect of galactosamine-induced hepatic UDP-glucuronic acid depletion on acetaminophen elimination in rats. Dispositional differences between hepatically and extrahepatically formed glucuronides of acetaminophen and other chemicals.

Galactosamine (GAL) markedly depletes hepatic UDP-glucuronic acid (UDP-GA) whereas extrahepatic UDP-GA is minimally affected. This suggests that GAL predominantly inhibits hepatic glucuronidation. Therefore, the effect of GAL-induced hepatic UDP-GA depletion was examined in bile duct-cannulated rats to determine the role of hepatic glucuronidation in the disposition of acetaminophen (AA). GAL markedly altered the fate of AA-glucuronide but had little or no effect upon other AA metabolites. GAL decreased the biliary excretion of AA-glucuronide up to 92%, whereas reductions in blood levels and urinary excretion of AA-glucuronide did not exceed 50%. This suggests that AA-glucuronide excreted in bile is predominantly of hepatic origin whereas AA-glucuronide found in blood and urine is derived from both hepatic and extrahepatic tissues. Data in the present and previous studies [Gregus, Watkins, Thompson, Klaassen: J. Pharmacol. Exp. Ther. 225, 256, (1983)] indicate that GAL greatly reduced the biliary excretion of AA- and valproic acid-glucuronide whereas the biliary excretion of the glucuronides of phenolphthalein, iopanoic acid, bilirubin, and diethylstilbestrol was only partially decreased. This difference appears to be largely due to differential contributions by the liver and extrahepatic tissues in the glucuronidation of various compounds as well as the availability of glucuronides formed in extrahepatic tissues for biliary excretion. Specifically, the extrahepatically formed glucuronide conjugates of AA and valproic acid are not readily available for biliary excretion whereas the glucuronides of the other compounds are readily excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

PubMed1988

Species variation in toxication and detoxication of acetaminophen in vivo: a comparative study of biliary and urinary excretion of acetaminophen metabolites.

Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42% of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7% of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic gamma-glutamyltranspeptidase activity; hamsters and mice (low gamma-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high gamma-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12% of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

PubMed1988

Interaction of caffeine with acetaminophen in mice: schedule dependency of the antagonism by caffeine of acetaminophen hepatotoxicity and the effects of caffeine metabolites, allopurinol, and diethyl ether.

Administration of caffeine (CAF) to mice as early as 6 hr prior to injection of a hepatotoxic but nonlethal dose of acetaminophen (ACM) significantly antagonized the hepatotoxic action of ACM as judged by serum levels of alanine aminotransferase (ALT) activity. Administration of CAF after ACM produced complete antagonism only when CAF was given no later than 1 hr after ACM. Administration of CAF daily for 3 days prior to injection of ACM enhanced ACM toxicity markedly, but little or no toxicity ensued when CAF-pretreated mice received ACM followed immediately by CAF. The four primary metabolites of CAF, 1,3-dimethylxanthine (theophylline), 3,7-dimethylxanthine (theobromine), 1,7-dimethylxanthine (paraxanthine), and 1,3,7-trimethyluric acid were effective and virtually complete antagonists of ACM-induced hepatotoxicity when given immediately after ACM, as were the secondary metabolites, 1-methylxanthine and 1,3-dimethyluric acid. Allopurinol, which reduces theophylline clearance, increases the rate of oxidative N-demethylation of theophylline to 1-methylxanthine, and inhibits conversion of 1-methylxanthine to 1-methyluric acid, was also a dose-dependent antagonist of ACM-induced hepatotoxicity. The hepatotoxic response of mice to ACM is exaggerated by a brief period of diethyl ether anesthesia; CAF given immediately after ACM to previously anesthetized mice suppressed this response and maintained serum ALT levels at control values. It is suggested that CAF and its primary metabolites compete with ACM for biotransformation by the cytochrome P-450 mixed function oxidase system, thereby reducing the rate of formation of the hepatotoxic ACM metabolite.

Acetaminophen↗

PubMedDate not supplied

3-Hydroxyacetaminophen: a microsomal metabolite of acetaminophen. Evidence against an epoxide as the reactive metabolite of acetaminophen.

3-Hydroxyacetaminophen has been isolated and identified as a microsomal metabolite of acetaminophen. Analysis of the metabolite by gas chromatography-mass spectrometry revealed that the metabolite had a molecular ion and fragmentation pattern identical to that of authentic 3-hydroxyacetaminophen. Glutathione and ascorbic acid blocked covalent binding of reactive metabolite(s) to protein but did not block the formation of 3-hydroxyacetaminophen. Moreover, epoxide hydrolase did not block covalent binding of the reactive metabolite(s) to protein. Thus, the reactive metabolite apparently is not an epoxide substrate of the hydrolase, nor are 3-hydroxyacetaminophen and the reactive metabolite(s) formed from a common intermediate.

Acetaminophen↗

PubMed1971