RT Journal Article
SR Electronic
T1 Disposition and Pharmacokinetics of the Antimigraine Drug, Rizatriptan, in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 89
OP 95
VO 28
IS 1
A1 Kamlesh P. Vyas
A1 Rita A. Halpin
A1 Leslie A. Geer
A1 Joan D. Ellis
A1 Lida Liu
A1 Haiyung Cheng
A1 Cynthia Chavez-Eng
A1 Bogdan K. Matuszewski
A1 Sandor L. Varga
A1 Alexander R. Guiblin
A1 J. D. Rogers
YR 2000
UL http://dmd.aspetjournals.org/content/28/1/89.abstract
AB 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