title: Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans.
abstract: The absorption and disposition of rizatriptan (MK-0462, Maxalt(TM)), a selective 5-HT(1B/1D) receptor agonist used in the treatment of migraine headaches, was investigated in humans. In a two-period, single i.v. (3 mg, 30-min infusion), and single oral (10 mg) dose study with [(14)C]rizatriptan in six healthy human males, total recovery of radioactivity was approximately 94%, with unchanged rizatriptan and its metabolites being excreted mainly in the urine (89% i.v. dose, 82% p.o. dose). Approximately 26 and 14% of i.v. and oral rizatriptan doses, respectively, were excreted in urine as intact parent drug. In a second, high-dose study (60 mg p.o.), five metabolites excreted into urine were identified using liquid chromatography-tandem mass spectrometry and NMR methods. They were triazolomethyl-indole-3-acetic acid, rizatriptan-N(10)-oxide, 6-hydroxy-rizatriptan, 6-hydroxy-rizatriptan sulfate, and N(10)-monodesmethyl-rizatriptan. Urinary excretion of triazolomethyl-indole-3-acetic acid after i.v. and oral administrations of rizatriptan accounted for 35 and 51% of the dose, respectively, whereas the corresponding values for rizatriptan-N(10)-oxide were 4 and 2% of the dose. Plasma clearance (CL) and renal clearance (CL(r)) were 1325 and 349 ml/min, respectively, after i.v. administration. A similar CL(r) value was obtained after oral administration (396 ml/min). The primary route of rizatriptan elimination occurred via nonrenal route(s) (i.e., metabolism) because the CL(r) of rizatriptan accounted for 25% of total CL. Furthermore, the CL(r) was higher than normal glomerular filtration rate ( approximately 130 ml/min), indicating that this compound was actively secreted by renal tubules. The absorption of rizatriptan was approximately 90%, but it experienced a moderate first-pass effect, resulting in a bioavailability estimate of 47%.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA. kamlesh_vyas@merck.com
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
authors.forename: R A
authors.initials: RA
authors.lastname: Halpin
authors.forename: L A
authors.initials: LA
authors.lastname: Geer
authors.forename: J D
authors.initials: JD
authors.lastname: Ellis
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.forename: C
authors.initials: C
authors.lastname: Chavez-Eng
authors.forename: B K
authors.initials: BK
authors.lastname: Matuszewski
authors.forename: S L
authors.initials: SL
authors.lastname: Varga
authors.forename: A R
authors.initials: AR
authors.lastname: Guiblin
authors.forename: J D
authors.initials: JD
authors.lastname: Rogers
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D002250:Carbon Radioisotopes / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D005243:Feces; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy; D012016:Reference Values; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D014018:Tissue Distribution; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D014363:Tryptamines
chemical_list: D002250:Carbon Radioisotopes; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; C093622:rizatriptan