The liver and small intestine are the major sites of biotransformation. Sufentanil is rapidly metabolized to a number of inactive metabolites, with oxidative N- and O-dealkylation being the major routes of elimination.
Although the metabolic fate of sufentanil in humans has not been fully characterized, the drug appears to be metabolized mainly in the liver and small intestine via N-dealkylation at the piperidine nitrogen and O-demethylation. The O-demethylated metabolite appears to have about 10% of the analgesic activity of the unchanged drug. The hepatic extraction ratio of the drug (EH) has been reported to be about 0.72 following IV administration of a single 5-mcg/kg dose.
IDENTIFICATION AND USE: Sufentanil is a solid. It is a Schedule II Controlled Substance. Sufentanil injection is used for intravenous administration as an analgesic adjunct in the maintenance of balanced general anesthesia in patients who are intubated and ventilated. In animals, sufentanil, like other opiate derivatives, is used for sedation, general anesthesia, and analgesia. HUMAN STUDIES: Acute overdose with sufentanil can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Sufentanil is a substance with a high potential for abuse similar to other opioids. ANIMAL STUDIES: Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day. Decreased live fetuses per litter and decreased litter size in the high dose group were noted. No malformations or embryotoxic effects were noted despite maternal toxicity. Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity. No evidence of malformations was reported in rats. Sufentanil 7.5 ug/kg intrathecally was neurotoxic in sheep. Sufentanil did not exhibit mutagenic activity in the Ames microbial mutagen test with metabolic activation. In female rats receiving single IV doses up to 80 ug/kg, sufentanil did not produce structural chromosome mutations in the micronucleus test.
Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Sufentanil's analgesic activity is, most likely, due to its conversion to morphine. Opioids open calcium-dependent inwardly rectifying potassium channels (OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. After epidural administration of incremental doses totaling 5 to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants.
来源:DrugBank
吸收、分配和排泄
消除途径
大约80%的给药剂量在24小时内被排出，只有2%的剂量以未改变的药物形式被消除。
Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.
Sufentanil has a distribution time of 1.4 minutes and redistribution time of 17.1 minutes. The central volume of distribution after intravenous application of sufentanil is approximately 14 L and the volume of distribution at steady state is approximately 350 L.
The total plasma clearance after single intravenous administration is about 917 l/min. The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease.
This randomized double-blind investigation was designed to study the placental transfer and neonatal effects of epidural sufentanil and fentanyl infused with bupivacaine for labor analgesia. Healthy parturient women (n = 36) received epidural bupivacaine alone (group B) or with fentanyl (group B-F) or sufentanil (group B-S). Group B received a 12-ml bolus of 0.25% bupivacaine followed by a 10 mL/hr infusion of 0.125% bupivacaine. Groups B-F and B-S received a 12-mL bolus of 0.125% bupivacaine with 75 ug fentanyl or 15 ug sufentanil, respectively, followed by 10 mL/hr of 0.125% bupivacaine with fentanyl 1.5 ug/mL or sufentanil 0.25 ug/mL. Maternal venous (MV) and umbilical arterial (UA) and umbilical venous (UV) bupivacaine and opioid plasma concentrations were determined. Neonatal assessment included Apgar scores, umbilical cord blood gas analyses, and neurobehavioral testing at delivery and at 2 and 24 hr of life using the Neurologic and Adaptive Capacity Score (NACS). The mean total dose of fentanyl was 136.6 +/- 13.1 micrograms (SEM), and of sufentanil, 23.8 +/- 1.8 micrograms. Although administered in a ratio of 5.7:1, fentanyl and sufentanil MV plasma concentrations were in the ratio of 27:1. UV/MV ratios were 0.37 for fentanyl and 0.81 for sufentanil. Fentanyl was detected in most UA samples, whereas sufentanil was present in only one sample. Neonatal condition was good and generally similar in all groups, with the exception of a lower NACS at 24 h in group B-F. Although the degree of placental transfer of sufentanil appeared greater than that of fentanyl, lower MV sufentanil concentrations resulted in less fetal exposure to sufentanil. The lower NACS at 24 hr in group B-F may reflect the continued presence of fentanyl in the neonate.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
3-Aminocyclopentanecarboxamides as modulators of chemokine receptors
申请人：Xue Chu-Biao
公开号：US20060004018A1
公开（公告）日：2006-01-05
The present invention is directed to compounds of Formula I:
which are modulators of chemokine receptors. The compounds of the invention, and compositions thereof, are useful in the treatment of diseases related to chemokine receptor expression and/or activity.
Benzoxazinyl-amidocyclopentyl-heterocyclic modulators of chemokine receptors
申请人：Goble D. Stephen
公开号：US20070238723A1
公开（公告）日：2007-10-11
Cyclopentyl compounds linked to a benzoxazinyl group through an amido moiety utilizing the ring nitrogen of the benzoxazine, and further substituted with a heterocyclic moiety, such compounds represented by formula I:
which are used to modulate the CCR-2 chemokine receptor to prevent or treat inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis; and pharmaceutical compositions comprising these compounds and the use of these compounds and compositions.
[EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
申请人：MERCK SHARP & DOHME
公开号：WO2013169567A1
公开（公告）日：2013-11-14
The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
