TY - JOUR T1 - Disposition and Pharmacokinetics of the Antimigraine Drug, Rizatriptan, in Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 89 LP - 95 VL - 28 IS - 1 AU - Kamlesh P. Vyas AU - Rita A. Halpin AU - Leslie A. Geer AU - Joan D. Ellis AU - Lida Liu AU - Haiyung Cheng AU - Cynthia Chavez-Eng AU - Bogdan K. Matuszewski AU - Sandor L. Varga AU - Alexander R. Guiblin AU - J. D. Rogers Y1 - 2000/01/01 UR - http://dmd.aspetjournals.org/content/28/1/89.abstract N2 - The absorption and disposition of rizatriptan (MK-0462, Maxalt™), a selective 5-HT1B/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 [14C]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-N10-oxide, 6-hydroxy-rizatriptan, 6-hydroxy-rizatriptan sulfate, andN10-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-N10-oxide were 4 and 2% of the dose. Plasma clearance (CL) and renal clearance (CLr) were 1325 and 349 ml/min, respectively, after i.v. administration. A similar CLr 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 CLr of rizatriptan accounted for 25% of total CL. Furthermore, the CLr was higher than normal glomerular filtration rate (∼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%. The American Society for Pharmacology and Experimental Therapeutics ER -