piperidines and eletriptan

Topics: Anticonvulsants; Botulinum Toxins; Calcitonin Gene-Related Peptide; Central Nervous System; Clinical Trials as Topic; Drug Design; Fructose; Humans; Indoles; Meta-Analysis as Topic; Migraine Disorders; Pain; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Signal Transduction; Sumatriptan; Topiramate; Triazoles; Trigeminal Nerve; Tryptamines; Vasodilation

Topics: Carbazoles; Evidence-Based Medicine; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1D; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Ergotamine; Humans; Ibuprofen; Indoles; Migraine Disorders; Naproxen; ortho-Aminobenzoates; Oxazolidinones; Piperidines; Pyrrolidines; Salicylates; Sumatriptan; Triazoles; Tryptamines

Topics: Acute Disease; Adult; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Child; Diclofenac; Drug Therapy, Combination; Ergotamine; Humans; Ibuprofen; Indoles; Migraine Disorders; Naproxen; ortho-Aminobenzoates; Oxazolidinones; Piperidines; Pyrrolidines; Salicylates; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Recent studies of the pathophysiology of migraine provide evidence that the headache phase is associated with multiple physiologic actions. These actions include the release of vasoactive neuropeptides by the trigeminovascular system, vasodilation of intracranial extracerebral vessels, and increased nociceptive neurotransmission within the central trigeminocervical complex. The 5-HT(1B/1D) receptor agonists, collectively known as triptans, are a major advance in the treatment of migraine. The beneficial effects of the triptans in patients with migraine are related to their multiple mechanisms of action at sites implicated in the pathophysiology of migraine. These mechanisms are mediated by 5-HT(1B/1D) receptors and include vasoconstriction of painfully dilated cerebral blood vessels, inhibition of the release of vasoactive neuropeptides by trigeminal nerves, and inhibition of nociceptive neurotransmission. The high affinity of the triptans for 5-HT(1B/1D) receptors and their favorable pharmacologic properties contribute to the beneficial effects of these drugs, including rapid onset of action, effective relief of headache and associated symptoms, and low incidence of adverse effects.

Topics: Carbazoles; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Triptans, beginning with sumatriptan, have revolutionized the treatment of migraine. New triptans in several formulations will soon become available in the United States. Although the similarities of these 5-hydroxytryptamine (5-HT) 1B/1D receptor agonists outweigh their differences, important differences in pharmacokinetics and clinical responses do exist. Subcutaneous sumatriptan has the most rapid onset of action and greatest efficacy but the most adverse effects. Intranasal sumatriptan also has rapid onset of action, but at 2 hours its efficacy is comparable to that of oral zolmitriptan. Of the oral triptans, rizatriptan seems to have the greatest early efficacy. Both rizatriptan and zolmitriptan are now available as rapidly dissolving wafers. Almotriptan, the newest of the triptans, has a response rate similar to that of oral sumatriptan and may produce fewer adverse effects. Naratriptan and frovatriptan, with their slow onset, high tolerability, and long half-lives, may have a role in aborting prolonged migraine attacks and in headache prevention. Eletriptan at higher doses (80 mg) has a response rate approaching that of rizatriptan but may be limited by potential side effects. The many triptans available offer the opportunity to individualize migraine treatment, depending on the patient's attack characteristics, tolerance, and preferences.

Topics: Carbazoles; Cardiovascular Diseases; Humans; Indoles; Migraine Disorders; Oxazolidinones; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

The current International Headache Society guidelines for migraine clinical trials recommend assessment of pain relief at 2 hours as a primary end point. Patients, however, express a clear preference for more rapid pain relief, with most patients defining rapid relief as occurring within 30 minutes after drug administration. Thus, consideration should be given to establishing clinical trial end points that more accurately reflect the preferences of patients with migraine. In this case, assessment of pain relief at 1 hour would be an appropriate primary end point. Using speed of relief as a criterion for migraine drug selection also is appropriate. The migraine-specific serotonin(1B/1D) agonists, or triptans, are able to meet this faster relief end point and are preferred by patients.

Topics: Analgesics, Non-Narcotic; Carbazoles; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Oxazolidinones; Pain Measurement; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Treatment Outcome; Triazoles; Tryptamines

The use of triptans has improved the ability to treat migraine successfully compared with older treatments. Speed of relief, consistency of effect, and good tolerability have been the hallmarks of these agents. All of the currently available triptans have comparable efficacy and tolerability. Variables between the agents may lead to one agent or dose form being preferred over another in various clinical scenarios. The triptans that are forthcoming may improve on these options through enhanced efficacy rates, tolerability, and headache recurrence rates. There exist increasing options for migraine treatment that may further improve the clinical effects of the older and newer triptans through early treatment of migraine at the stages of mild migraine pain, or even during the prodromal phase of the attack. Additionally, recent work suggests that mini-prophylaxis of migraine at the menses is a highly successful treatment option with the triptans. In this age of managed care, providing cost-effective treatment of headache will take on increasing importance. Techniques such as stratification of acute treatments may enhance cost-effective care, whereas ready availability of the triptans may lead to significant improvements in utilization of parameters such as office visits, emergency room treatment, and even hospitalization.

Topics: Acute Disease; Blood Flow Velocity; Carbazoles; Clinical Trials as Topic; Drug Administration Routes; Female; Humans; Indoles; Male; Menstruation; Migraine Disorders; Oxazolidinones; Piperidines; Practice Guidelines as Topic; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Vasoconstriction; Vasoconstrictor Agents

Sterile neurogenic inflammation within cephalic tissue, involving vasodilation and plasma protein extravasation, has been proposed as a pathophysiological mechanism in acute migraine. The action of 5-hydroxytryptamine (5-HT1B/1D) agonists--so-called triptans--on receptors located in meningeal arteries (5-HT1B) and trigeminovascular fiber endings (5-HT1D) has an inhibitory effect on this neurogenic inflammation. Recently, a series of second-generation 5-HT1B/1D agonists (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan) have been developed and are reviewed in this article. Their in vitro pharmacological properties, pharmacokinetics, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the golden standard in the treatment of acute migraine, sumatriptan.

Topics: Acute Disease; Carbazoles; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Triazoles; Tryptamines

The efficacy of 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) agonists is related to their inhibitory effects on neurogenic inflammation, mediated through serotoninergic control mechanisms. Recently, a series of oral second generation 5-HT 1B/1D agonists (eletriptan, naratriptan, rizatriptan and zolmitriptan) have been developed and are reviewed in this paper. Their in vitro and in vivo pharmacological properties, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the gold standard in the treatment of acute migraine, sumatriptan.

Topics: Acute Disease; Animals; Clinical Trials as Topic; Coronary Circulation; Coronary Vasospasm; Drug Design; Drug Interactions; Humans; Inactivation, Metabolic; Indoles; Meninges; Migraine Disorders; Molecular Structure; Nociceptors; Oxazoles; Oxazolidinones; Piperidines; Propranolol; Pyrrolidines; Randomized Controlled Trials as Topic; Rats; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Recurrence; Serotonin Receptor Agonists; Structure-Activity Relationship; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Vasoconstrictor Agents

Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.. To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated.. Our calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration.. These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Topics: Humans; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Serotonin 5-HT1 Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

This was a randomized, double-blind study designed to evaluate the comparative efficacy and tolerability of the 40-mg dose of eletriptan and the 2.5-mg dose of naratriptan. Patients (n = 548) meeting International Headache Society (IHS) criteria for migraine were randomized to treat a single migraine attack with either eletriptan 40 mg, naratriptan 2.5 mg, or placebo. Headache response rates at 2 h and 4 h, respectively, were 56% and 80% for eletriptan, 42% and 67% for naratriptan (P < 0.01 for both time-points vs. eletriptan), and 31% and 44% for placebo (P < 0.0001 vs. both active drugs at both time-points). Eletriptan also showed a significantly greater pain-free response at 2 h (35% vs. 18%; P < 0.001) as well as lower use of rescue medication (15% vs. 27%; P < 0.01) and higher sustained headache response at 24 h (38%) compared with naratriptan (27%; P < 0.05) and placebo (19%; P < 0.01). Both eletriptan and naratriptan were well tolerated. The results confirm previous meta-analyses that have suggested the superiority of eletriptan vs. naratriptan in the acute treatment of migraine.

Topics: Adult; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Tryptamines

Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the excretion of six different triptans into milk. Following intake of a single dose, each participant collected seven breast milk samples at predefined intervals up to 24 hours after dose. Triptan concentrations in milk were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infant drug exposure was estimated by calculating the relative infant dose (RID). Twenty-two breast milk sample sets were obtained for sumatriptan (n = 8), rizatriptan (n = 5), zolmitriptan (n = 4), eletriptan (n = 3), almotriptan (n = 1) and naratriptan (n = 1). Based on the average concentration in milk throughout the day, estimated mean RIDs (with range in parenthesis) were as follows: eletriptan 0.6% (0.3%-0.8%), sumatriptan 0.7% (0.2%-1.8%), rizatriptan 0.9% (0.3%-1.4%), almotriptan 1.8% (-), zolmitriptan 2.1% (0.7%-5.3%) and naratriptan 5.0% (-). Infant drug exposure through breastfeeding appears to be low and indicates that use of the triptans in this study is compatible with breastfeeding. Naratriptan may not be first choice in breastfeeding mothers initiating triptans during the neonatal period.

Topics: Adult; Breast Feeding; Female; Humans; Infant; Infant, Newborn; Migraine Disorders; Milk, Human; Oxazolidinones; Piperidines; Pyrrolidines; Triazoles; Tryptamines

Authors developed a simple, sensitive, selective, rapid, rugged, and reproducible liquid chromatography-tandem mass spectrometry method for the quantification of eletriptan (EP) in human plasma using naratriptan (NP) as an internal standard (IS). Chromatographic separation was performed on Ascentis Express C18, 50 × 4.6 mm, 2.7 μm column. Mobile phase was composed of 0.1% formic acid: methanol (40:60 v/v), with 0.5 mL/min flow rate. Drug and IS were extracted by liquid-liquid extraction. EP and NP were detected with proton adducts at m/z 383.2→84.3 and 336.2→97.8 in multiple reaction monitoring (MRM) positive mode, respectively. The method was validated with the correlation coefficients of (r(2)) ≥ 0.9963 over a linear concentration range of 0.5-250.0 ng/mL. This method demonstrated intra- and inter-day precision within 1.4-9.2% and 4.4-5.5% and accuracy within 96.8-103% and 98.5-99.8% for EP. This method is successfully applied in the bioequivalence study of 24 human volunteers.

Topics: Chromatography, High Pressure Liquid; Humans; Liquid-Liquid Extraction; Piperidines; Pyrrolidines; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Serotonin Receptor Agonists; Tandem Mass Spectrometry; Tryptamines

The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database.. Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to "drug abuse," "physical or mental drug dependence," and "pharmacodependence," whereas "non-cases" were defined as all the remaining SED reports. The method's reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%.. Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8-22.3] for sumatriptan to 21.5 for eletriptan [10.1-45.6], while in the ergot derivative group, it ranged from 12 [8-17.9] for ergotamine to 20.6 [8-53] for dihydroergotamine.. These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.

Topics: Claviceps; Dihydroergotamine; Ergotamine; Humans; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Risk; Substance-Related Disorders; Sumatriptan; Tryptamines

Molecules of eletriptan hydrobromide monohydrate (systematic name: (1S,2R)-1-methyl-2-{5-[2-(phenylsulfonyl)ethyl]-1H-indol-3-ylmethyl}pyrrolidinium bromide monohydrate), C(22)H(27)N(2)O(2)S(+) x Br(-) x H(2)O, (I), and naratriptan hydrochloride (systematic name: 1-methyl-4-{5-[2-(methylsulfamoyl)ethyl]-1H-indol-3-yl}piperidinium chloride), C(17)H(26)N(3)O(2)S(+) x Cl(-), (II), adopt conformations similar to other triptans. The C-2 and C-5 substituents of the indole ring, both of which are in a region of conformational flexibility, are found to be oriented on either side of the indole ring plane in (I), whilst they are on the same side in (II). The N atom in the C-2 side chain is protonated in both structures and is involved in the hydrogen-bonding networks. In (I), the water molecules create helical hydrogen-bonded chains along the c axis. In (II), the hydrogen bonding of the chloride ions results in macrocyclic R(4)(2)(20) and R(4)(2)(24) ring motifs that form sheets in the bc plane. This structural analysis provides an insight into the molecular structure-activity relationships within this class of compound, which is of use for drug development.

Topics: Analgesics; Crystallography, X-Ray; Halogens; Humans; Hydrogen Bonding; Migraine Disorders; Molecular Structure; Piperidines; Pyrrolidines; Salts; Structure-Activity Relationship; Tryptamines

Topics: Acetaminophen; Age Factors; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Child; Ergot Alkaloids; Humans; Ibuprofen; Life Style; Migraine Disorders; Oxazolidinones; Parents; Patient Education as Topic; Pediatrics; Piperidines; Pyrrolidines; Risk Factors; Serotonin Receptor Agonists; Sumatriptan; Taste Disorders; Triazoles; Tryptamines; Vasoconstrictor Agents

Managed care and other decision makers need sound comparative information to support the formulary selection process and reimbursement decisions for the treatment of migraine. The objective of this study was to compare currently marketed triptan therapies using number-needed-to-treat (NNT) and doses-needed-to-treat (DNT) measures. DNT was further used to derive triptan treatment cost to achieve 100 successfully treated patients such that the cost-effectiveness of each treatment regime could be compared from the payer perspective.. Using published meta-analysis data to categorize patients as treatment success or failure, an NNT and a DNT were derived for each triptan. Treatment success was defined as achieving a 2-hour pain response, sustained through 24 hours postdose. Costs were derived by multiplying DNT by the average wholesale price (AWP) minus 15% for each triptan.. Eletriptan 40 mg had the lowest NNT, with 361 patients needing to be treated in order to have 100 patients achieve clinical benefit; rizatriptan 5 mg had the highest NNT (597 patients). Eletriptan 40 mg required 388 doses to successfully treat 100 patients.the lowest number of doses of the triptans considered; rizatriptan 5 mg required the highest number (662 doses). Eletriptan 40 mg had the lowest total triptan cost of USD 5,630 to successfully treat 100 patients. The highest total triptan cost of treatment was USD 11,136 for naratriptan 2.5 mg.. Eletriptan 40 mg provides the best value in terms of the lowest DNT, assuming an approximately equal AWP discount for each triptan. Eletriptan 40 mg also was found to have the lowest total triptan cost to successfully treat 100 patients. Future research should further explore the utility of DNT in managed care decision making.

Topics: Algorithms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Humans; Managed Care Programs; Migraine Disorders; Piperidines; Pyrrolidines; Recurrence; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Triazoles; Tryptamines

Migraine pain arises in the trigeminovascular system and is often associated with nausea and sometimes with vomiting. In this study, an in vivo cat model of trigeminovascular stimulation was used to determine first whether there is a functional connection between the trigeminovascular system and the nucleus tractus solitarius (NTS), which is involved in regulating vomiting, and second whether anti-migraine drugs have any effect on such a connection. Chloralose-anaesthetised cats (n=16) were prepared for single neuron recording. The superior sagittal sinus (SSS) was isolated and stimulated electrically. The brainstem near the obex was exposed and a metal microelectrode equipped with six glass barrels for microiontophoresis was placed in the NTS. Recordings were made from 44 NTS neurons which responded to SSS stimulation with A-delta latencies. Iontophoretic ejection (50 nA) of eletriptan or naratriptan suppressed the response in 75% (15/20) and 78% (11/14) of cells and caused an average suppression of cell firing of 42+/-5% (n=20) and 54+/-8% (n=14), respectively. This suppression could be antagonized by the concurrent ejection (20-50 nA) of the 5-HT(1B/1D) receptor antagonist GR127935. We conclude that activation of the trigeminovascular system excites cells in the NTS that can be inhibited by eletriptan and naratriptan through activation of 5-HT(1B/1D) receptors. It is possible that in patients having a migraine attack trigeminovascular activation triggers nausea and vomiting, and that the alleviation of these symptoms by anti-migraine compounds may be via an action at 5-HT(1B/1D) receptors in the NTS.

Topics: Action Potentials; Animals; Cats; Drug Interactions; Electric Stimulation; Indoles; Maximum Tolerated Dose; Neural Inhibition; Oxadiazoles; Piperazines; Piperidines; Pyrrolidines; Reaction Time; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists; Solitary Nucleus; Trigeminal Nuclei; Tryptamines

Using a series of triptans we characterized in vitro the 5-hydroxytryptamine (5-HT) receptor that mediates the contraction in guinea-pig iliac arteries moderately precontracted by prostaglandin F2alpha (PGF2alpha). Additionally, we investigated by reverse-transcriptase polymerase chain reaction (RT-PCR) which triptan-sensitive receptor is present in this tissue. Frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, and almotriptan contracted guinea-pig iliac arteries with pD2 values of 7.52+/-0.04, 6.72+/-0.03, 6.38+/-0.06, 6.22+/-0.05, 5.86+/-0.05 and 5.26+/-0.04 respectively. For comparison, the pD2 values for 5-HT and 5-carboxamidotryptamine (5-CT) were 7.52+/-0.02 and 7.55+/-0.03 respectively. In contrast to all other triptans tested, the concentration-response curve for eletriptan was biphasic (first phase: 0.01-3 microM, pD2 approximately 6.6; second phase: > or = 10 microM). Contractions to 5-HT, 5-CT, frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, almotriptan, and eletriptan (first phase) were antagonized by the 5-HT1B/1D receptor antagonist GR127935 (10 nM) and the 5-HT1B receptor antagonist SB216641 (10 nM). RT-PCR studies in guinea-pig iliac arteries showed a strong signal for the 5-HT1B receptor while expression of 5-HT1D and 5-HT1F receptors was not detected in any sample. The present results demonstrate that triptan-induced contraction in guinea-pig iliac arteries is mediated by the 5-HT1B receptor. The guinea-pig iliac artery may be used as a convenient in vitro model to study the (cardio)vascular side-effect potential of anti-migraine drugs of the triptan family.

Topics: Animals; Benzamides; Brain; Carbazoles; Dinoprost; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelium, Vascular; Female; Forecasting; Guinea Pigs; Iliac Artery; Indoles; Ketanserin; Male; Muscle Contraction; Muscle, Smooth; Oxadiazoles; Oxazolidinones; Piperazines; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Sumatriptan; Triazoles; Tryptamines

"Reaction phenotyping" studies were performed with eletriptan (ETT) to determine its propensity to interact with coadministered medications. Its ability to serve as a substrate for human P-glycoprotein (P-gp) was also investigated since a central mechanism of action has been proposed for this "triptan" class of drug. In studies with a characterized bank of human liver microsome preparations, a good correlation (r2 = 0.932) was obtained between formation of N-desmethyl eletriptan (DETT) and CYP3A4-catalyzed testosterone 6 beta-hydroxylation. DETT was selected to be monitored in our studies since it represents a significant ETT metabolite in humans, circulating at concentrations 10 to 20% of those observed for parent drug. ETT was metabolized to DETT by recombinant CYP2D6 (rCYP2D6) and rCYP3A4, and to a lesser extent by rCYP2C9 and rCYP2C19. The metabolism of ETT to DETT in human liver microsomes was markedly inhibited by troleandomycin, erythromycin, miconazole, and an inhibitory antibody to CYP3A4, but not by inhibitors of other major P450 enzymes. ETT had little inhibitory effect on any of the P450 enzymes investigated. ETT was determined to be a good substrate for human P-gp in vitro. In bidirectional transport studies across LLC-MDR1 and LLC-Mdr1a cell monolayers, ETT had a BA/AB transport ratio in the range 9 to 11. This finding had significance in vivo since brain exposure to ETT was reduced 40-fold in Mdr1a+/+ relative to Mdr1a-/- mice. ETT metabolism to DETT is therefore catalyzed primarily by CYP3A4, and plasma concentrations are expected to be increased when coadministered with inhibitors of CYP3A4 and P-gp activity.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Brain; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Erythromycin; Genes, MDR; Humans; Indoles; Injections, Intravenous; Male; Mice; Mice, Mutant Strains; Miconazole; Microsomes, Liver; Oxazolidinones; Oxidoreductases, N-Demethylating; Phenotype; Piperidines; Pyrrolidines; Recombinant Proteins; Statistics as Topic; Sumatriptan; Triazoles; Troleandomycin; Tryptamines

Topics: Administration, Oral; Controlled Clinical Trials as Topic; Delayed-Action Preparations; Female; Headache; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Placebos; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Tryptamines

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

The affinity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]-1H-indole) for a range of 5-HT receptors was compared to values obtained for other 5-HT1B/1D receptor agonists known to be effective in the treatment of migraine. Eletriptan, like sumatriptan, zolmitriptan, naratriptan and rizatriptan had highest affinity for the human 5-HT1B, 5-HT1D and putative 5-ht1f receptor. Kinetic studies comparing the binding of [3H]eletriptan and [3H]sumatriptan to the human recombinant 5-HT1B and 5-HT1D receptors expressed in HeLa cells revealed that both radioligands bound with high specificity (>90%) and reached equilibrium within 10-15 min. However, [3H]eletriptan had over 6-fold higher affinity than [3H]sumatriptan at the 5-HT1D receptor (K(D)): 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [3H]sumatriptan at the 5-HT1B receptor (K(D): 3.14 and 11.07 nM, respectively). Association and dissociation rates for both radioligands could only be accurately determined at the 5-HT1D receptor and then only at 4 degrees C. At this temperature, [3H]eletriptan had a significantly (P<0.05) faster association rate (K(on) 0.249 min(-1) nM(-1)) than [3H]sumatriptan (K(on) 0.024 min(-1) nM(-1)) and a significantly (P<0.05) slower off-rate (K(off) 0.027 min(-1) compared to 0.037 min(-1) for [3H]sumatriptan). These data indicate that eletriptan is a potent ligand at the human 5-HT1B, 5-HT1D, and 5-ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache.

Topics: Animals; Binding, Competitive; Cell Line; Cold Temperature; COS Cells; HeLa Cells; Humans; Indoles; Kinetics; Oxazoles; Oxazolidinones; Piperidines; Pyrrolidines; Radioligand Assay; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Sumatriptan; Triazoles; Tritium; Tryptamines