Monitoring patients taking methotrexate for hepatotoxicity. Does the standard of care match published guidelines?

BACKGROUND: Controversy persists regarding the validity of published guidelines for the monitoring of methotrexate-induced hepatotoxicity. OBJECTIVE: The purpose of our study was to assess the standard of care by gastroenterologists in the monitoring of methotrexate-induced hepatotoxicity and to compare this standard of care with guidelines in the medical literature. METHODS: Gastroenterologists in Connecticut and Massachusetts were surveyed by a mail-in questionnaire that inquired about their protocol for the monitoring of hepatotoxicity in patients taking methotrexate. RESULTS: Gastroenterologists in Connecticut and Massachusetts generally follow the guidelines in the medical literature. Variation in recommendations from the rheumatologic and the dermatologic literature is reflected in the practice habits of gastroenterologists whose patients are restricted to one particular population. CONCLUSION: Long-term follow-up studies should be continued to obtain further data from which to make future recommendations, especially with regard to the effects of large cumulative doses of methotrexate.

Biological activity of the fatty acid ester metabolites of corticoids.

Fatty acid esters of all families of steroid hormones are known to exist naturally. While their physiological roles are not clear, the C-17-fatty acid esters of estradiol are extremely potent and unusually long-lived estrogens. Thus, it appeared that increased potency would be a logical consequence of the esterification of all of the active steroid hormones. To test this hypothesis we measured the effect of an ester of corticosterone, corticosterone-21-stearate, on the induction of tyrosine aminotransferase in adrenalectomized rats. Surprisingly, while the ester is active compared to the unesterified corticoid corticosterone, there was no difference in either the magnitude or the duration of the induction of this enzyme. To determine whether the C-21-steroidal ester could itself induce this gluconeogenic response, we tested corticosterone-21-oleate and corticosterone-21-stearate as competitors for the binding of [3H] dexamethasone to the glucocorticoid receptor in rat liver cytosol. Both were poor ligands, with binding affinities of about 4% and more than 1%, respectively, compared to corticosterone. From these results, it is doubtful that the esters could act directly in vivo without prior cleavage of the fatty acid. We measured the rate of hydrolysis of corticosterone-21-stearate and estradiol-17-stearate by rat liver esterases. Corticosterone-21-stearate is hydrolyzed at a much greater rate (10- to 25-fold) than estradiol-17-stearate. Consequently, the difference in both potency and duration of response between the ester of the corticoid and that of the estrogen can be explained by the very rapid rate of conversion of the former into the unesterified form. Since the esterification of the corticoids appears not to be related to an increased biological half-life, as it is in the estrogens, the question remains as to the physiological role that they might play.