Ergotamine, particularly the peptide portion of the molecule, is extensively metabolized in the liver by the cytochrome P-450 (CYP) enzyme system, mainly by the 3A4 isoenzyme; 90% of the metabolites are excreted in bile.
This study investigated if genetic differences exhibited in endophyte-resistant and -susceptible mouse lines had persisted after 13 generations in which the integrity of lines was maintained yet selection ceased. Experimental groups were mouse lines fed an endophyte-free (E-) or -infected (E+) diet. The in vitro metabolism of the ergot alkaloid ergotamine in mouse liver microsomes was characterized by LC-MS/MS and compared between both lines before and after exposure to E+ feed. ... Microsomal incubations produced nine predominate peaks in the HPLC assay. The peaks were confirmed by LC-MS/MS to be ergotamine, ergotamine epimer, monohydroxylated metabolites (M1, M2, M1e, M2e) and dihydroxylated metabolites (M3--5). A gender difference for metabolite formation was observed on the E- diet, in that females produced a greater amount of M1, M1e and M3--5 than males. When challenged with the E+ diet, mice showed differences in concentration of M3 for line (resistant > susceptible) and gender (female > male) and of M4 and M5 for gender (female > male). Gender differences in the metabolism of ergotamine have not been shown before in these lines of mice or other species used to study ergot alkaloid metabolism. ...
IDENTIFICATION AND USE: Ergotamine tartrate is used to prevent or abort vascular headaches, including migraine and cluster headaches. It is also used in veterinary medicine. HUMAN STUDIES: There have been reports of drug abuse and psychological dependence in patients on ergotamine tartrate therapy. In addition to the adverse effects which may occur with usual doses or prolonged administration of high doses (especially adverse vasospastic effects, nausea, and vomiting), acute overdosage of ergotamine may cause lassitude, impaired mental function, confusion, depression, drowsiness, delirium, severe dyspnea, hypotension, hypertension, rapid and weak pulse, unconsciousness, spasms of the limbs, seizures (rarely), shock, and death. Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine induces vasoconstriction by a direct action on vascular smooth muscle. In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains, numbness, coldness, and pallor of the digits may occur. If the condition is allowed to progress untreated, gangrene can result. Nausea and vomiting, due to a direct effect on CNS emetic centers, occur in approximately 10% of patients after oral administration of ergotamine, and in about twice that number after parenteral administration. Leg weakness is common, and muscle pains that occasionally are severe may occur in the extremities. Numbness and tingling of the fingers and toes are other reminders of the ergotism that this alkaloid may cause. Precordial distress and pain suggestive of angina pectoris, as well as transient tachycardia or bradycardia, also have been noted, presumably as a result of coronary vasospasm induced by ergotamine. Ergotamine has been tested for its ability to induce chromosomal damage in human lymphocyte cells. Treatment with 0.1, 0.25 and 0.5 ug/mL significantly increased frequency of aberrations. Ergotamine is contraindicated in pregnant women. ANIMAL STUDIES: It is suggested that dietary ergotamine is atherogenic in the rabbit. Daily oral doses of 1.0 mg/kg of ergotamine tartrate resulted in death of 4 of 6 sheep in 10 days. Postmortem exam revealed intestinal inflammation. 0.5 mg/day over a period of 10 days was not fatal. Extended exposure of bulls to ergotamine appeared to reduce fertilization potential of sperm. Single-day oral treatment of rats with ergotamine (10 mg/kg) causes fetal deaths. In early pregnancy, from days 4-10, mortality was only 0-11%, and on days 14 and 15, 62% and 59% respectively. Typical anomalies resulting from "edema syndrome" were seen only on days 13-16. Male mice were injected with 25, 50 and 100 mg/kg ergotamine, and significant number of chromosome aberrations were observed with higher doses. Almost all damage was in form of chromatid aberrations. Dominant lethal test with mice using ergotamine was negative in doses up to 100 mg/kg. Several accidental poisonings in cows were described in the literature.
◉ Summary of Use during Lactation:There is limited published experience with ergotamine during breastfeeding and it might cause adverse effects in the infant and decrease milk supply. Most authorities consider ergotamine to be contraindicated during nursing.
◉ Effects in Breastfed Infants:A study in which ergotamine was administered to mothers of newborns immediately postpartum in a dose of 1 mg 3 times daily for 6 days found no effect on weight gain in the breastfed infants. Milk intake, and therefore infant dosage, might have been minimal during the first few days before the mothers' milk came in fully.
◉ Effects on Lactation and Breastmilk:Thirty women who delivered fullterm infants received a single intramuscular dose of methylergonovine 0.2 mg after delivery, followed by oral ergotamine 1 mg 3 times daily for 6 days. Compared to 28 women who delivered fullterm infants and received no ergot derivatives, there was no difference in the milk production, as measured by weight differences before and after nursing, between the 2 groups during the first 6 days postpartum.
来源:Drugs and Lactation Database (LactMed)
毒理性
副作用
神经毒素 - 其他中枢神经系统神经毒素
Neurotoxin - Other CNS neurotoxin
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Coadministration of ergotamine with potent CYP 3A4 inhibitors such as protease inhibitors or macrolide antibiotics has been associated with serious adverse events; for this reason, these drugs should not be given concomitantly with ergotamine. While these reactions have not been reported with less potent CYP 3A4 inhibitors, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine. Examples of less potent CYP 3A4 inhibitors include: saquinavir, nefazodone, fluconazole, fluoxetine, grapefruit juice, fluvoxamine, zileuton, metronidazole, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with ergotamine.
Ergomar Sublingual Tablets (Ergotamine Tartrate Sublingual Tablets USP) should not be administered with other vasoconstrictors. Use with sympathomimetics (pressor agents) may cause extreme elevation of blood pressure. The beta-blocker Inderal (propranolol) has been reported to potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics and vasospastic reactions have been reported with therapeutic doses of the ergotamine-containing drugs when coadministered with these antibiotics.
Following oral administration, absorption of ergotamine tartrate is quite variable; peak plasma concentrations are attained within 0.5-3 hours. Orally administered ergotamine tartrate undergoes first-pass metabolism.
The unchanged drug is erratically secreted in the saliva and only traces of unchanged drug are excreted in urine and feces. Following a single oral dose of ergotamine in individuals with normal renal and hepatic function in one study, only about 4% of the dose was excreted in urine within 96 hours; the remainder of the dose was presumably excreted in feces. Ergotamine is eliminated by dialysis.
