Fospropofol is metabolized into propofol, formaldehyde, and phosphate by endothelial alkaline phosphatase. The metabolite, formaldehyde, is quickly oxidized into formic acid by glutathione dependent and independent dehydrogenases and erythrocytes. Excess formic acid is eliminated via oxidation to carbon dioxide through the tetrahydrofolate pathway. Propofol is further metabolized into propofol glucuronide, quinol-4-sulfate, quinol-1-fluronide, and quinol-4-glucuronide. The cytochrome P450 enzyme system is not involved with the metabolism of fospropofol.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：根据药物导致人类肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
◉ Summary of Use during Lactation:No information is available on the clinical use of fospropofol during breastfeeding. However, fospropofol is rapidly metabolized to propofol in the body. Amounts of propofol in milk are very small and are not expected to be absorbed by the infant. Although one expert panel recommends withholding nursing for an unspecified time after propofol administration, most recommend that breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia to nurse and that discarding milk is unnecessary. When a combination of anesthetic agents is used for a procedure, follow the recommendations for the most problematic medication used during the procedure. General anesthesia for cesarean section using propofol as a component for induction may delay the onset of lactation. In one study, breastfeeding before general anesthesia induction reduced requirements of propofol and sevoflurane compared to those of nursing mothers whose breastfeeding was withheld or nonnursing women. Case reports have noted green discoloration of breastmilk after nursing mothers received propofol.
◉ Effects in Breastfed Infants:Four mothers who were breastfeeding their infants received propofol as part of their general anesthesia for surgical procedures. All patients also received intravenous remifentanil and rocuronium, and inhaled xenon as part of the anesthesia. They were given doses of propofol that targeted a serum concentration of 6.5 mcg/L for induction and stopped as xenon anesthesia was started. Operation times ranged from 35 to 45 minutes. Individual infants were first breastfed as follows: 1.5 hours, 2.8 hours, 4.6 hours, and 5 hours after extubation. No signs of sedation were observed in any of the infants.
◉ Effects on Lactation and Breastmilk:Five women who were 6 to 15 weeks postpartum were given single doses of 2 mg of midazolam and 2.5 mg/kg of propofol intravenously before undergoing general anesthesia. The women's milk output following the surgical procedure was less than half of the normal milk output of nursing mothers. The authors speculated that milk volume might be reduced postoperatively because of perioperative fluid restriction and volume losses, as well as stress-induced inhibition of milk production.
A woman underwent emergency laparoscopic surgery using propofol as well as fentanyl, remifentanil, mivacurium, and dipyrone during the surgery and metamizole, piritramide, dipyrone, butylscopolamine, and metoclopramide postoperatively. Eight hours postoperatively, her milk turned bluish green, then green. Both propofol and metoclopramide have caused green urine. Thirty hours after the milk color change, propofol but not metoclopramide, was detected in milk.
A randomized study compared the effects of cesarean section using general anesthesia, spinal anesthesia, or epidural anesthesia, to normal vaginal delivery on serum prolactin and oxytocin as well as time to initiation of lactation. General anesthesia was performed using propofol 2 mg/kg and rocuronium 0.6 mg/kg for induction, followed by sevoflurane and rocuronium 0.15 mg/kg as needed. Fentanyl 1 to 1.5 mcg/kg was administered after delivery. Patients in the general anesthesia group (n = 21) had higher post-procedure prolactin levels and a longer mean time to lactation initiation (25 hours) than in the other groups (10.8 to 11.8 hours). Postpartum oxytocin levels in the nonmedicated vaginal delivery group were higher than in the general and spinal anesthesia groups.
A randomized, double-blind study compared the effects of intravenous propofol 0.25 mg/kg, ketamine 0.25 mg/kg, ketamine 25 mg plus propofol 25 mg, and saline placebo for pain control in mothers post-cesarean section in mothers post-cesarean section. A single dose was given immediately after clamping of the umbilical cord. The time to the first breastfeeding was 58 minutes in those who received placebo, 42.6 minutes with propofol and 25.8 minutes with propofol plus ketamine. The time was significantly shorter than the other groups with the combination.
A retrospective study of women in a Turkish hospital who underwent elective cesarean section deliveries compared women who received bupivacaine spinal anesthesia (n = 170) to women who received general anesthesia (n = 78) with propofol for induction, sevoflurane for maintenance and fentanyl after delivery. No differences in breastfeeding rates were seen between the groups at 1 hour and 24 hours postpartum. However, at 6 months postpartum, 67% of women in the general anesthesia group were still breastfeeding compared to 81% in the spinal anesthesia group, which was a statistically significant difference.]
A woman nursing an 8-month-old infant 6 to 8 times daily was admitted to the hospital for an appendectomy. During the procedure she received cefazolin, granisetron, ketorolac, rocuronium, succinylcholine, and sufentanil. The patient also received 2 boluses of intravenous propofol of 150 mg followed shortly thereafter by a 50 mg dose. Postoperatively, she was receiving acetaminophen, cefazolin, ibuprofen, and pantoprazole, as well as oxycodone and dimenhydrinate as needed. Twenty-two hours after the procedure, the mother extracted milk for the first time and noted it to be light green in color. Analysis of the green milk using a nonvalidated assay detected no propofol. The green color faded and was absent by postoperative day 4 when she resumed breastfeeding. The authors judged that the green color was possibly caused by propofol or one of its metabolites.
A pregnant woman had an emergency cesarean section delivery in her 24th week of gestation. During the procedure she received 200 mg of propofol as well as cefazolin and acetaminophen after delivery. The first milk expressed by the mother at 12 hours after the procedure was dark green. At 30 hours after the procedure is was light green and returned to a normal color by hour 48.
Adequate sedation achieved after 7 minutes with a IV bolus dose of 10mg/kg. It takes 21-45 minutes for patients to recover for fospropopol-induced sedation. Following an intravenous bolus administration of 6 mg/kg in a healthy subject, the pharmacokinetic parameters of fospropofol are as follows: Cmax = 78.7 μg/mL; Tmax = 4 minutes; AUC(0-∞) = 19.0 μg ⋅ h/mL;
Chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. There is negligible renal elimination of unchanged fospropofol (<0.02%).
[EN] WATER SOLUBLE PRODRUGS OF HINDERED ALCOHOLS OR PHENOLS<br/>[FR] PROMÉDICAMENTS SOLUBLES DANS L'EAU À FONCTION ALCOOL OU PHENOL MASQUÉ
申请人：UNIV KANSAS
公开号：WO2000008033A1
公开（公告）日：2000-02-17
The present invention is directed to novel water-soluble prodrugs of aliphatic or aromatic hindered hydroxyl group containing pharmaceuticals.
本发明涉及一种新型水溶性脂肪族或芳香族受阻羟基含药物的前药。
Water soluble prodrugs of hindered alcohols
申请人：Universtiy of Kansas
公开号：US06204257B1
公开（公告）日：2001-03-20
The present invention is directed to novel water-soluble prodrugs of aliphatic or aromatic hindered hydroxyl group containing pharmaceuticals.
本发明涉及含有脂肪族或芳香族受阻羟基的药物的新型水溶性前药。
Process for preparing water-soluble phosphonooxymethyl derivatives of alcohol and phenol
申请人：Bonneville George
公开号：US20070043206A1
公开（公告）日：2007-02-22
A process for making water-soluble phosphonooxymethyl ethers of hindered alcohol and phenol containing pharmaceuticals, such as camptothecin, propofol, etoposide, Vitamin E and Cyclosporin A. In particular, the process for preparing water-soluble phosphonooxymethyl derivatives comprises the steps of:
R—OH represents an alcohol- or phenol-containing drug, n represents an integer of 1 or 2, R
1
is hydrogen, an alkali metal ion, or a pharmaceutically acceptable cation, and R
2
is hydrogen, an alkali metal ion, or a pharmaceutically acceptable cation.
Pharmaceutical compositions containing water-soluble prodrugs of propofol and methods of administering same
申请人：Eisai Inc.
公开号：EP2281565A2
公开（公告）日：2011-02-09
The present invention is directed to pharmaceutical compositions containing water-soluble prodrugs of propofol and methods of administering the prodrug. In one aspect, a method of inducing and/or maintaining a generalized anesthetic state comprises administering by parenteral infusion a prodrug of propofol in an amount sufficient to cause and/or maintain loss of consciousness. In another aspect, a prodrug of propofol is administered for producing a sedated state in a subject.
Carboxylic acid derivatives and use thereof in the preparation of prodrugs
申请人：Li Qingeng
公开号：US10239851B2
公开（公告）日：2019-03-26
The present invention discloses a class of carboxylic acid derivatives and use thereof in preparation of prodrugs. The carboxylic acid derivatives have the general formula (I), wherein R1 is H or alkyl; X is H or F; Y is F or fluoroalkyl; n is 0, 1, 2, 3, 4, 5, or 6; W is W1 or W2; W1 is NR2R3, NR2R3.A,
R2 and R3 are each independently H, alkyl, cycloalkyl, or a protecting group for amino; m is 0, 1, 2, or 3; A is an acid; W2 is COOR4, OPO(OR4)2, or PO(OR)2; R4 is H, or a protecting group for carboxyl or hydroxyl in phosphoric acid.
本发明公开了一类羧酸衍生物及其在制备原药中的用途。这些羧酸衍生物具有通式（I），其中 R1 是 H 或烷基；X 是 H 或 F；Y 是 F 或氟烷基；n 是 0、1、2、3、4、5 或 6；W 是 W1 或 W2；W1 是 NR2R3、NR2R3.A.、NR2R3.B.、NR2R3.C.、NR2R3.D.、
R2 和 R3 各自独立地为 H、烷基、环烷基或氨基的保护基团；m 为 0、1、2 或 3；A 为酸；W2 为 COOR4、OPO(OR4)2 或 PO(OR)2；R4 为 H 或磷酸中羧基或羟基的保护基团。
