Abstract
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%.
Footnotes
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Send reprint requests to: Kamlesh P. Vyas, Ph.D., Department of Drug Metabolism, Merck Research Laboratories, Merck and Co., Inc., WP75A-203, West Point, PA 19486. E-mail:kamlesh_vyas{at}merck.com
- Abbreviations used are::
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- CL
- plasma clearance
- CLr
- renal clearance
- TFA
- trifluoroacetic acid
- CID
- collision-induced dissociation
- AUC
- area under the plasma concentration-time profile from time zero to time infinity
- Vss
- steady-state volume of distribution
- Received June 28, 1999.
- Accepted October 8, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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