title: Identification and human pharmacokinetics of dihydroergotoxine metabolites in man: preliminary results.
abstract: Dihydroergotoxine is a mixture of semi-synthetic ergot alkaloids mainly used for age-related cognitive impairment. In this study, dihydroergotoxine (30 microM) was added to incubates of rat and bovine liver microsomes, and the resulting major metabolites were identified as hydroxy-dihydroergocornine, hydroxy-dihydroergocryptine and hydroxy-dihydroergocristine on the basis of molecular mass measurements, determined with a time-of-flight mass spectrometer. The relevance of these to humans was then investigated by simultaneously monitoring dihydroergotoxine and its hydroxy-metabolites in human plasma by LC-MS/MS after oral dosing of dihydroergotoxine mesylate (27 mg) to a healthy volunteer (male, age 45, height 1.93 m, weight 103 kg). In this preliminary approach, the peaks (C(max)) of dihydroergocornine, dihydroergocryptine and dihydroergocristine were about 0.04 microg/l. The peaks (C(max)) of their hydroxy-metabolites were 0.98, 0.53 and 0.30 microg/l, respectively. In conclusion, in this preliminary approach it was found that hydroxy-dihydroergocornine, hydroxy-dihydroergocryptine and hydroxy-dihydroergocristine were one order of magnitude higher in concentration than their parents in human plasma.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, PO BOX 6111, 13084-971, Campinas - SP, Brazil.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bicalho
authors.forename: Juliana Marconi
authors.initials: JM
authors.lastname: Giolo
authors.forename: Sergio
authors.initials: S
authors.lastname: Lilla
authors.forename: Gilberto
authors.initials: G
authors.lastname: De Nucci
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D025441:Dihydroergocornine / Q000737:chemistry / Q000378:metabolism; D025442:Dihydroergocristine / Q000737:chemistry / Q000378:metabolism; D025443:Dihydroergocryptine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D004877:Ergoloid Mesylates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D015394:Molecular Structure; D008970:Molecular Weight; D051381:Rats; D013607:Tablets; D053719:Tandem Mass Spectrometry; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D013607:Tablets; D014665:Vasodilator Agents; C527876:beta-dihydroergocryptine; D025442:Dihydroergocristine; D025443:Dihydroergocryptine; D004877:Ergoloid Mesylates; D025441:Dihydroergocornine