{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:41:42Z","timestamp":1790685702830,"version":"4.1.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[1999,11,1]],"date-time":"1999-11-01T00:00:00Z","timestamp":941414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Doxorubicin is an effective anticancer agent that is limited by numerous adverse effects, cardiotoxicity causing the most concern. Its alcohol metabolite, doxorubicinol, and free radicals have been implicated in the aetiology of this toxicity. This study was based on the premise that inhibition of aldo-keto reductases would improve the efficacy of doxorubicin by reducing its toxic metabolites and modifying its pharmacokinetics. We assessed the effect of in-vitro inhibition of aldo-keto reductases on the metabolism of doxorubicin in cytosolic fractions of heart and liver of rats in the presence of Na-phenobarbital.<\/jats:p>\n               <jats:p>The inhibition was confirmed by a significant reduction in the formation of doxorubicinol. The results of the in-vitro study were further evaluated in-vivo. The concentrations of doxorubicin in plasma, bile and urine and its major metabolites in bile and urine were measured in Na-phenobarbital-pretreated rats. Each rat received 100 mg kg\u22121\/day intraperitoneal injection of sodium phenobarbital for three days followed by a single intravenous dose of 10 mg kg\u22121 [14C-14]doxorubicin (sp. act. 0.2 \u03bcCi mg\u22121) on the fourth day. The levels of drug in all biological samples were measured by HPLC. The pretreatment resulted in an increase in biological half-life (5.8 \u00b1 1.5 vs 3.7 \u00b1 0.93 h control group, P &amp;lt; 0.05) and area under plasma concentration-time curve (19.6 \u00b1 1.7 vs 14.65 \u00b1 1.68 mg h L\u22121 control group, P &amp;lt; 0.05). The cumulative amount of doxorubicinol in the bile and urine of pretreated animals was reduced significantly. In terms of % dose, the amount in the bile declined from 4.2 \u00b1 0.8% in control to 2.4 \u00b1 0.3% and in urine from 0.18 \u00b1 0.08% to 0.12 \u00b1 0.07%. There were no significant changes in doxorubicin aglycone and doxorubicinol aglycone. Serum creatine kinase levels were measured as a biomarker of damage to cardiac muscle. The area under creatine kinase level-time curve was reduced by approximately 50% in phenobarbital-pretreated animals.<\/jats:p>\n               <jats:p>The results indicate that the inhibition of aldo-keto reductase could provide a useful approach to improve the safety of doxorubicin by reducing its alcohol metabolite. Furthermore, if the reduction in the area under the serum creatine kinase-time curve represents a reduced damage to heart muscle, it can be concluded that doxorubicinol plays an important role in this injury.<\/jats:p>","DOI":"10.1211\/0022357991777010","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T22:04:05Z","timestamp":1033509845000},"page":"1275-1282","source":"Crossref","is-referenced-by-count":38,"title":["Inhibition of Aldo-keto Reductases by Phenobarbital Alters Metabolism, Pharmacokinetics and Toxicity of Doxorubicin in Rats"],"prefix":"10.1093","volume":"51","author":[{"given":"Kamelia","family":"Behnia","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeastern University , Boston, MA 02115,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Boroujerdi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeastern University , Boston, MA 02115,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[1999,11,1]]},"reference":[{"key":"2024103110045812600_cit1","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1016\/0006-2952(78)90047-3","article-title":"Heterogeneity of anthracycline antibiotic carbonyl reductases in mammalian livers","volume":"27","author":"Ahmed","year":"1978","journal-title":"Biochem. Pharmacol."},{"key":"2024103110045812600_cit2","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1007\/s002800050753","article-title":"Investigation of the enterohepatic recirculation of adriamycin and its metabolites by a linked-rat model","volume":"41","author":"Behnia","year":"1998","journal-title":"Cancer Chemother. Pharmacol."},{"key":"2024103110045812600_cit3","doi-asserted-by":"crossref","first-page":"4480","DOI":"10.1016\/S0021-9258(19)45010-2","article-title":"Triphosphopyridine nucleotide-linked aldehyde reductase","volume":"274","author":"Bosron","year":"1972","journal-title":"J. Biol. Chem."},{"key":"2024103110045812600_cit4","first-page":"677","article-title":"In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol by rat","volume":"207","author":"Boyd","year":"1978","journal-title":"Lung and liver micro-somes"},{"key":"2024103110045812600_cit5","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1111\/j.1471-4159.1973.tb07525.x","article-title":"Partial purification and characterisation of NADPH-linked aldehyde reductase from monkey brain","volume":"21","author":"Bronaugh","year":"1973","journal-title":"J. Neurochem."},{"key":"2024103110045812600_cit6","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1002\/1097-0142(19850615)55:12<2761::AID-CNCR2820551206>3.0.CO;2-P","article-title":"Early and delayed clinical cardiotoxicity of doxorubicin","volume":"55","author":"Buzdar","year":"1985","journal-title":"Cancer"},{"key":"2024103110045812600_cit7","first-page":"967","article-title":"General and cardiac toxicity of adriamycinol in rat","volume":"6","author":"Danesi","year":"1986","journal-title":"Anticancer Res."},{"key":"2024103110045812600_cit8","first-page":"1073","article-title":"Might adriamycinol contribute to adriamycin-induced cardiotoxicity? Pharmacol","volume":"17","author":"del Tacca","year":"1985","journal-title":"Res. Commun."},{"key":"2024103110045812600_cit9","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1172\/JCI110328","article-title":"Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine","volume":"68","author":"Doroshow","year":"1981","journal-title":"J. Clin. Invest."},{"key":"2024103110045812600_cit10","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1111\/j.1471-4159.1972.tb01280.x","article-title":"Purification and characterisation of an NADH-linked aldehyde reductase from bovine brain","volume":"19","author":"Erwin","year":"1972","journal-title":"J. Neurochem."},{"key":"2024103110045812600_cit11","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/0006-2952(77)90054-5","article-title":"Rat liver aldehyde reductase","volume":"26","author":"Felsted","year":"1977","journal-title":"Biochem. Pharmacol."},{"key":"2024103110045812600_cit12","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/978-3-642-77763-9_15","article-title":"Cytochrome P450 in rodents","volume-title":"Cytochrome P450, Handbook of Experimental Pharmacology","author":"Funae","year":"1993"},{"key":"2024103110045812600_cit13","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1016\/0006-2952(87)90240-1","article-title":"Metabolism of adriamycin in hepatocytes isolated from the rat and the rabbit","volume":"36","author":"Gewirtz","year":"1987","journal-title":"Biochem. Pharmacol."},{"key":"2024103110045812600_cit14","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/S0006-2952(96)00564-3","article-title":"Effect of psychotropic drugs on aldo-keto reductase activity in rat ovary and adrenal gland","volume":"52","author":"Inazu","year":"1996","journal-title":"Biochem. Pharmacol."},{"key":"2024103110045812600_cit15","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/0003-9861(76)90302-7","article-title":"Partial purification of the NADPH-dependent aldehyde reductase from bovine cardiac muscle","volume":"173","author":"Kawalek","year":"1976","journal-title":"Arch. Biochem. Biophys."},{"key":"2024103110045812600_cit16","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S0735-1097(87)80099-2","article-title":"Alterations in left ventricular diastolic function with doxorubicin therapy","volume":"9","author":"Lee","year":"1987","journal-title":"J. Am. Coll. Cardiol."},{"key":"2024103110045812600_cit17","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2","article-title":"Clinicopathologic analysis of adriamycin cardiotoxicity","volume":"32","author":"Lefrak","year":"1973","journal-title":"Cancer"},{"key":"2024103110045812600_cit18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/BF02353864","article-title":"Comparison of the Akaike information criterion, the Schwarz criterion and the F-Test as guide to model selection","volume":"22","author":"Ludden","year":"1994","journal-title":"J. Pharmacokin. Biopharm."},{"key":"2024103110045812600_cit19","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1172\/JCI117833","article-title":"Secondary alcohol metabolites mediate iron de-localisation in cystolic fraction of myocardial biopsies exposed to anticancer anthracyclines. Novel link between anthracycline metabolism and iron-induced cardiotoxicity","volume":"95","author":"Minotti","year":"1995","journal-title":"J. Clin. Invest."},{"key":"2024103110045812600_cit20","first-page":"45","article-title":"Anthracyclines","volume-title":"Cancer Chemotherapy and Biological Modifiers Annual 13","author":"Myers","year":"1992"},{"key":"2024103110045812600_cit21","first-page":"1011","volume":"34","author":"Mylari","year":"1991","journal-title":"A highly specific aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate, and its congeners."},{"key":"2024103110045812600_cit22","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.1073\/pnas.85.10.3585","article-title":"Doxorubicin cardiotoxicity may be caused by its metabolite doxorubicinol","volume":"85","author":"Olson","year":"1988","journal-title":"Proc. Natl Acad. Sci."},{"key":"2024103110045812600_cit23","first-page":"106","article-title":"Toxicity of free radical forming anticancer drugs","volume-title":"The Toxicity of Anticancer Drugs","author":"Powis","year":"1991"},{"key":"2024103110045812600_cit24","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1016\/S0021-9258(17)40492-3","article-title":"Resolution and partial characterisation of two aldehyde reductases of mammalian liver","volume":"252","author":"Tulsiani","year":"1977","journal-title":"J. Biol. Chem."},{"key":"2024103110045812600_cit25","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1111\/j.2042-7158.1996.tb03934.x","article-title":"Pharmacokinetic-toxicodynamic relationships of adriamycin in rat: prediction of butylated hydroxyanisole-mediated reduction in anthracyclin cardiotoxicity","volume":"48","author":"Vora","year":"1996","journal-title":"J. Pharm. Pharmacol."},{"key":"2024103110045812600_cit26","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1042\/bj2810577","article-title":"Phenobarbital induction of cytochrome P-450 gene expression","volume":"281","author":"Waxman","year":"1992","journal-title":"Biochem. J."}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1211%2F0022357991777010","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/51\/11\/1275\/60263047\/0022357991777010.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/51\/11\/1275\/60263047\/0022357991777010.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T10:40:02Z","timestamp":1730371202000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/51\/11\/1275\/6157416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,11,1]]},"references-count":26,"journal-issue":{"issue":"11","published-online":{"date-parts":[[1999,11,1]]},"published-print":{"date-parts":[[1999,11,1]]}},"URL":"https:\/\/doi.org\/10.1211\/0022357991777010","relation":{},"ISSN":["0022-3573","2042-7158"],"issn-type":[{"value":"0022-3573","type":"print"},{"value":"2042-7158","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[1999,11]]},"published":{"date-parts":[[1999,11,1]]}}}