Physicochemical, pharmacological, and pharmacokinetic properties of selected 5-HT1B/1D agonists
Compound Dose | mol. wt. | fu a | 5-HT1B Potencyb | 5-HT1D Potencyb | Human Pharmacokinetic Parametersc | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
Total Cmax |
fu Cmax |
Total AUC
|
fu AUC
| ||||||||
| pEC50 | pEC50 | ng/ml | nM | ng · h/ml | nM · h | ||||||
| Doses that provide superior efficacy to SUMA100d | |||||||||||
| ETT80 | 382 | 0.24 | 7.7 ± 0.02 | 9.2 ± 0.02 | 226 | 142 | 1486 | 934 | |||
| ZOLM5 | 287 | 0.75 | 7.6 ± 0.05 | 8.9 ± 0.06 | 7.3-9.1 | 19-24 | 52-62 | 136-162 | |||
| RIZA10 | 269 | 0.86 | 7.1 ± 0.04 | 8.4 ± 0.05 | 19.8 | 63 | 49.6 | 158 | |||
| Doses that provide equivalent efficacy to SUMA100d | |||||||||||
| SUMA100 | 295 | 0.82 | 7.0 ± 0.03 | 8.3 ± 0.05 | 54-78 | 150-216 | 419 | 1164 | |||
|
ETT40
|
382
|
0.24
|
7.7 ± 0.02
|
9.2 ± 0.02
|
113
|
71
|
743
|
467
| |||
↵ a Plasma protein binding (PPB) for ETT was reported as 76% by Morgan et al. 1997, which was in agreement with an in-house determination of PPB for 200 ng/ml ETT of 75 ± 3%. PPB data for ZOLM, RIZA, and SUMA were abstracted from the product labels [Product Information for Rizatriptan, Merck and Co. Inc., West Point, PA, (1998); Product Information for Sumatriptan; Glaxo Wellcome Inc., Research Triangle Park, NC (1998); Product Information for Zolmitriptan, AstraZeneca Pharmaceuticals LP, Wilmington, DE (1998)]. The reported value of PPB for SUMA was also in agreement with the value determined in-house (17 ± 4%).
↵ b 5-HT1B/1D potency data were abstracted from Stewart et al. (1999).
↵ c Pharmacokinetic data were abstracted from Palmer and Spencer (1997) for ZOLM, Sciberras et al. (1997) for RIZA, and Perry and Markham (1998) for SUMA. Pharmacokinetic data for ETT40 and ETT80 were approximated by pro-rating data from an oral dose ranging study that used 15, 20, 30, 60, 90, and 120 mg of ETT (Milton et al., 2002); ETT Cmax = 2.828 · Dose (r2 = 0.96), ETT AUC = 18.577 · Dose (r2 = 0.97).
↵ d ETT80, ZOLM5, and RIZA 10 provided equivalent efficacy and were superior to SUMA 100 with respect to percentage of patients free from headache at 2 h and patients with improvements in headache at 2 h (Goadsby et al., 2002). Using these efficacy criteria, ETT40 was equivalent to SUMA 100.