Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, inhumans

The absorption and disposition of rizatriptan (MK-0462, Maxalt(TM)), a sele ctive 5-HT1B/1D receptor agonist used in the treatment of migraine headache s, was investigated in humans. In a two-period, single i.v. (3 mg, 30-min i nfusion), and single oral (10 mg) dose study with [C-14]rizatriptan in six healthy human males, total recovery of radioactivity was approximately 94%, with unchanged rizatriptan and its metabolites being excreted mainly in th e urine (89% i.v. dose, 82% p.o. dose). Approximately 26 and 14% of i.v. an d oral rizatriptan doses, respectively, were excreted in urine as intact pa rent drug. In a second, high-dose study (60 mg p.o.), five metabolites excr eted into urine were identified using liquid chromatography-tandem mass spe ctrometry and NMR methods. They were triazolomethyl-indole-3-acetic acid, r izatriptan-N-10-oxide, 6-hydroxy-rizatriptan, 6-hydroxy-rizatriptan sulfate , and N-10-monodesmethyl-rizatriptan. Urinary excretion of triazolomethyl-i ndole-3-acetic acid after i.v. and oral administrations of rizatriptan acco unted for 35 and 51% of the dose, respectively, whereas the corresponding v alues for rizatriptan-N-10-oxide were 4 and 2% of the dose. Plasma clearanc e (CL) and renal clearance (CLr) were 1325 and 349 ml/min, respectively, af ter i.v. administration. A similar CLr value was obtained after oral admini stration (396 ml/min). The primary route of rizatriptan elimination occurre d via nonrenal route(s) (i.e., metabolism) because the CLr of rizatriptan a ccounted for 25% of total CL. Furthermore, the CLr was higher than normal g lomerular filtration rate (similar to 130 ml/min), indicating that this com pound was actively secreted by renal tubules. The absorption of rizatriptan was approximately 90%, but it experienced a moderate first-pass effect, re sulting in a bioavailability estimate of 47%.