Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation. Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine. [Naloxone] undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group.
来源:DrugBank
代谢
丁丙诺啡有人类已知的代谢物，包括去甲丁丙诺啡和丁丙诺啡葡萄糖苷酸。
Buprenorphine has known human metabolites that include Norbuprenorphine and Buprenorphine glucuronide.
Buprenorphine therapy has been associated with a low rate of serum enzyme elevations during treatment, although the populations studied (opioid dependent) often have coexisting chronic liver diseases which complicate such assessments. Nevertheless, rates of ALT elevations during treatment with buprenorphine (with or without naloxone) have been minimally or no greater than with comparator arms (methadone).
In addition, there have been several reports and case series of acute, clinically apparent liver injury arising within 2 to 20 weeks of starting buprenorphine, usually (but not invariably) following misuse and intravenous administration of sublingual tablets. However, some cases occurred in patients who denied intravenous use and were on conventional sublingual doses. In most cases, the pattern of serum enzyme elevations was hepatocellular and the presentation resembled acute toxic hepatic necrosis. Immunoallergic features (fever, rash and eosinophilia) were not present, nor were autoantibodies detected. Almost all patients with this injury had concurrent chronic hepatitis C, and several appeared to resolve the chronic infection with the acute liver injury (Case 1). Strikingly, most patients were able to continue buprenorphine without recurrence, some of whom admitted to continued intravenous abuse.
Likelihood score: B[HD] (likely rare cause of clinically apparent liver injury usually associated with overdose or misuse).
◉ Summary of Use during Lactation:Because of the low levels of buprenorphine in breastmilk, its poor oral bioavailability in infants, and the low drug concentrations found in the serum and urine of breastfed infants, its use is acceptable in nursing mothers. Monitor the infant for drowsiness, respiratory depression, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. Although unlikely, if the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Observe infants for withdrawal signs if breastfeeding is stopped abruptly.
Women who received buprenorphine for opiate abuse during pregnancy and are stable should be encouraged to breastfeed their infants postpartum, unless there is another contraindication, such as use of street drugs. The long-term outcome of infants breastfed during maternal buprenorphine therapy for opiate abuse has not been well studied. The breastfeeding rate among mothers taking buprenorphine for opiate dependency may be lower than in other mothers; however, among women taking buprenorphine as part of an abstinence program, the retention rate may be better in nursing mothers than in non-breastfeeding mothers.
◉ Effects in Breastfed Infants:Numerous infants have been reported to breastfeed during maternal narcotic abstinence therapy with buprenorphine with no adverse effects, one for 6 months. The amounts of buprenorphine in milk may not be sufficient to prevent neonatal withdrawal, and treatment of infant may be required.
Despite breastfeeding and relatively high infant serum drug levels, mild buprenorphine withdrawal occurred in the neonate of a mother taking buprenorphine 4 mg daily (route not specified) during pregnancy and postpartum for heroin dependency. This indicates that an insufficient dosage appeared in milk to prevent neonatal abstinence.
Ten women who had undergone cesarean section delivery of term newborns were given extradural buprenorphine 200 mcg followed by 8.4 mcg/hour with an anesthetic for postoperative pain for 3 days postpartum. A control group of 10 other women were given extradural anesthetic only without buprenorphine. Over 11 days postpartum, newborns of mothers in the buprenorphine group had much lower milk intake and lower weight gain than those in the non-buprenorphine group. The authors suggested that extradural buprenorphine suppressed infant breastfeeding. Infant neurobehavioral assessments were not performed.
Six infants whose mothers were taking buprenorphine during pregnancy and postpartum were breastfed. Four of the infants had signs of opioid abstinence, indicating that the amounts of buprenorphine in breastmilk were inadequate to prevent withdrawal. At 1 month after discharge from the hospital, all infants had normal development and weight gain.
Seven infants who averaged 1.12 months of age (range 0.58 to 1.85 months) were being breastfed by mothers taking buprenorphine for opiate substitution during pregnancy and lactation. Urine screening indicated that 4 mothers had also been using cannabis, 1 was using unprescribed benzodiazepines, and 1 mother was using both cannabis and benzodiazepines. Four of the infants were exclusively breastfed and 3 were mostly breastfed. Infants had no apparent drug-related adverse effects and showed satisfactory developmental progress.
A mother used buprenorphine (dose and indication not stated) during pregnancy. Her infant displayed no signs of neonatal abstinence at birth. The infant was breastfed (extent not stated) until 4 months of age when the mother stopped breastfeeding. Two days later the infant had withdrawal symptoms including frequent yawning, sneezing, pupillary dilation, agitation, sweating, hyperactive Moro reflex, myoclonic jerks, tremors, and insomnia. The infant was given methadone with immediate improvement of her withdrawal symptoms. The infant’s withdrawal symptoms were probably caused by abrupt withdrawal of breastfeeding.
In a study of 7 women taking buprenorphine in a median dose of 7 mg daily (range 2.4 to 24 mg daily) , breastfed infants were followed-up at 3 and 4 weeks of age. Four infants were exclusively breastfed and 3 were partially breastfed. At the follow-up visits, infants were assessed for weight gain, sleeping patterns, skin color, and elimination and hydration patterns. All infants had values within normal limits for these parameters at follow-up.
A cohort of 124 infants exposed during pregnancy to maternal medication for opioid maintenance therapy were followed postpartum in a Norwegian study. Forty-six infants were born to mothers taking buprenorphine. Overall, infants who were breastfed had a lower rate of neonatal abstinence symptoms and a shorter duration of therapy for neonatal abstinence. However, the differences were not statistically significant for the subset of infants whose mothers took buprenorphine.
A study of pregnant women being treated for opiate dependency with buprenorphine at a clinic in Vienna were followed as were their newborn infants. No difference was found between breastfed (n = 31) and nonbreastfed infant (n = 41) in average measures of neonatal abstinence, dosage requirements of morphine, durations of treatment for neonatal abstinence or durations of hospital stays.
A statewide retrospective database study found that infants diagnosed with NAS spent a median of 2 days less in the hospital if they were breastfed than those who were not breastfed.
The results of two multicenter cohort studies were compared. The original study had 86 newborns with neonatal abstinence and the second had 113 infants. All infants had been exposed to methadone or buprenorphine in utero. Infants who were breastfed had a shorter hospitalization by 4.5 to 7.5 days than infants who were not breastfed. Infants who were exposed to buprenorphine had a shorter hospitalization by 4 to 5 days than those exposed to methadone.
A study of 89 pregnant women were treated with buprenorphine for maintenance of opioid abstinence. Fewer of their infants who were exclusively breastfed required morphine for neonatal abstinence symptoms than those who were not exclusively breastfed. Exclusively breastfed infants had an earlier time to peak abstinence symptoms and fewer days in the hospital than the nonexclusively breastfed infants.
A 2-week-old infant was brought to the emergency department for drowsiness and poor feeding. He was lethargic and had pinpoint pupils upon admission, with a Glasgow coma score of 5 and blood glucose of 79 mg/dL. Two doses of naloxone 0.15 mg resulted in infant crying and improved tone. The infant’s mother had been taking buprenorphine 8 mg twice daily for several months for opioid use disorder. She was exclusively breastfeeding and denied illicit drug use. After admission to the hospital, the infant has several episodes of hypoglycemia and required another dose of naloxone for bradycardia, lethargy and pinpoint pupils with some improvement. Breastfeeding was stopped and the infant developed mild withdrawal symptoms that did not require treatment. The infant’s symptoms were probably caused by buprenorphine, but the contribution by breastfeeding cannot be differentiated from prenatal exposure.
◉ Effects on Lactation and Breastmilk:Buprenorphine can increase serum prolactin. However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In a multicenter prospective study of 246 pregnant women receiving either methadone or buprenorphine for opiate dependency, 153 women were receiving high-dose buprenorphine. Twenty-two percent of women receiving buprenorphine breastfed their infants, which was the same percentage as those receiving methadone.
A retrospective chart review of 276 opiate-dependent mothers who delivered in a Baby Friendly Hospital found that mothers taking buprenorphine or methadone for opiate dependency were unlikely to breastfeed their infants. Only 45% of the 20 mothers on buprenorphine maintenance initiated breastfeeding. Of all women in the study, 60% discontinued breastfeeding before discharge from the hospital.
A retrospective case series reported on 85 opioid-dependent women maintained on buprenorphine during pregnancy and postpartum during the period of December 2007 to August 2012. Of these women, 65 were breastfeeding on discharge from the hospital and 66% of these were breastfeeding at their 6- to 8-week follow-up appointment (extent of nursing not stated).
A retrospective cohort study in Australia compared breastfeeding rates on discharge of drug-using mothers who were taking either buprenorphine, other opiates or nonopioids (e.g., benzodiazepines, amphetamines, cocaine, alcohol, inhalants, cannabinoids, psychotropics). Breastfeeding rates at discharge from the hospital were as follows: buprenorphine 27%, other opiates 31%, and nonopioids 51%.
A small retrospective study found that only 3 of 10 pregnant women treated with buprenorphine plus naloxone for opioid dependence were breastfeeding their infants at the time of hospital discharge.
A retrospective cohort study of 150 women enrolled in a substance abuse treatment program found that women taking methadone had a higher prevalence of breastfeeding than women taking buprenorphine plus naloxone. However, this difference appeared to be related to the greater intention to breastfeed before delivery in the methadone group.
A retrospective cohort study of 228 women enrolled in a perinatal substance abuse treatment program found that women taking buprenorphine had a higher prevalence of breastfeeding than women taking methadone. The intention to breastfeed before delivery was similar in both groups.
A systematic review of studies on the effect of breastfeeding on the outcomes of infants whose mothers were taking methadone during pregnancy and postpartum concluded that the association between newborn feeding method and neonatal abstinence syndrome among newborns exposed to buprenorphine in breastmilk was unclear.
A retrospective chart review of 64 mothers given buprenorphine postpartum for opioid use disorder found that mothers who breastfed their infants were more likely to attend a follow-up appointment within 10 to 14 weeks postpartum.
A small retrospective study of 19 mothers with for opiate use disorder found that mothers who were taking buprenorphine were more likely to breastfeed their infants than mothers taking methadone (70% vs 29%).
◈ What is buprenorphine?
Buprenorphine is an opioid medication. Opioids are sometimes called narcotics. Buprenorphine is used to treat addiction to opioid drugs (such as heroin) and narcotic painkillers. It has also been used to treat pain. It is available as an injection (including brand names Buprenex® and Sublocade®), an oral film that dissolves in the mouth (Belbuca®), and a patch worn on the skin (Butrans®). Buprenorphine is also available in different forms combined with the medication naloxone (such as Bunavail®, Suboxone®, and Zubsolv®).
◈ I am taking buprenorphine, but I would like to stop taking it before becoming pregnant. How long does the medication stay in my body?
Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.People get rid of medications from their bodies at different rates. In healthy, non-pregnant adults, it takes up to 9 days, on average, for most of the buprenorphine to be gone from the body. It may take a longer time for long-acting (extended-release) medications.
◈ I just found out I am pregnant. Should I stop taking buprenorphine?
No. If you have been taking buprenorphine regularly you should not stop suddenly (also called “cold turkey”). Stopping an opioid medication suddenly could cause you to go into withdrawal. More research is needed to know how going through withdrawal might affect a pregnancy. Talk with your healthcare providers before making any changes to your medications. Changes to your buprenorphine treatment during pregnancy or while breastfeeding should be done only under the care of your healthcare provider.
◈ I take buprenorphine. Can it make it harder for me to get pregnant?
Studies have not been done to see if taking buprenorphine can make it harder to get pregnant.
◈ Does taking buprenorphine increase the chance of miscarriage?
Miscarriage can occur in any pregnancy. Limited studies looking at buprenorphine use in pregnancy have not found higher rates of miscarriage than what is seen in the general population. However, there are no published studies looking specifically at whether buprenorphine increases the chance of miscarriage. Based on the studies reviewed, it is not known if buprenorphine increases the chance for miscarriage.
◈ Does taking buprenorphine increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Limited studies looking at buprenorphine in pregnancy have not reported an increased chance for birth defects. Not every opioid medication has been studied on its own. Some studies that have looked at opioids as a group suggest that opioids in general might be associated with birth defects. However, studies have not found a specific pattern of birth defects caused by opioids. Based on these studies, if there is an increased chance for birth defects with opioid use in pregnancy, it is likely to be small.
◈ Does taking buprenorphine in pregnancy increase the chance of other pregnancy-related problems?
When taken as prescribed, buprenorphine is not expected to increase the chance for pregnancy problems. Studies involving people who often use some opioids during their pregnancy have found an increased chance for poor pregnancy outcomes such as poor growth of the baby, stillbirth, delivery before 37 weeks of pregnancy (preterm delivery), and C-section. This is more commonly reported in those who are taking a drug like heroin or who are using prescribed pain medications in higher amounts or for longer than recommended by their healthcare provider. Use of an opioid close to the time of delivery can result in withdrawal symptoms in the baby (see the section of this fact sheet on Neonatal Abstinence Syndrome).
◈ Will my baby have withdrawal (Neonatal Abstinence Syndrome) if I continue to take buprenorphine?
Studies have reported that some babies will experience neonatal abstinence syndrome (NAS) when buprenorphine is used up to the time of delivery.NAS is the term used to describe withdrawal symptoms in newborns from medication(s) that a person takes during pregnancy. For any opioid, symptoms can include difficulty breathing, extreme drowsiness (sleepiness), poor feeding, irritability, sweating, tremors, vomiting and diarrhea. NAS symptoms from buprenorphine may not appear for several days after birth and may last more than two weeks. Most babies can be successfully treated for withdrawal while in the hospital. If you use opioids, it is important that your baby’s healthcare providers know, so they cancheck for symptoms of NAS.
◈ Does taking buprenorphine in pregnancy affect future behavior or learning for the child?
Based on the studies reviewed, there is not enough information to know if buprenorphine increases the chance for behavior or learning issues. Some studies on opioids as a general group have found more problems with learning and behavior in children exposed to opioids for a long period of time during pregnancy. It is hard to tell if this is due to the medication exposure or other factors such as use of tobacco, alcohol, and/or other substances that can increase the chances of these problems.
◈ What if I have been taking more buprenorphine than recommended by my healthcare provider?
Studies find that pregnant women who misuse opioids have an increased chance for pregnancy problems. These include poor growth of the baby, stillbirth, premature delivery, and the need for C-section. Some women who misuse opioids also have unhealthy lifestyles that can result in health problems for both the mother and the baby. For example, poor diet choices can lead to mothers not having enough nutrients to support a healthy pregnancy and could increase the chance of miscarriage and premature birth. Sharing needles to inject opioids increases the risk of getting diseases like hepatitis C and/or HIV which can also infect the baby.
◈ Breastfeeding while taking buprenorphine:
Buprenorphine gets into breastmilk in low amounts. Talk with your healthcare provider or a MotherToBaby specialist about your medication, as information on breastfeeding might change based on your specific situation such as the age of your baby, the dose and delivery type of the medication (injection, oral film, patch), and other factors.Use of some opioids in breastfeeding might cause babies to be very sleepy and have trouble latching on. Some opioids can cause trouble with breathing. Talk to your healthcare provider about how to monitor (watch) your baby for any signs of concern while you are taking buprenorphine. Contact the baby’s healthcare provider right away if you suspect the baby has any problems such as increased sleepiness (more than usual), trouble feeding, trouble breathing, or limpness. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male takes buprenorphine, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if buprenorphine could affect male fertility or increase the chance of birth defects. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.
来源:Mother To Baby Fact Sheets
毒理性
蛋白质结合
丁丙诺啡大约有96%与蛋白质结合，主要与α-和β-球蛋白结合。
Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin.
Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation. Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0.5mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine.
Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine). The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter.
Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk.
Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901.2 ± 39.7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 mL/min.
[EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2010104818A1
公开（公告）日：2010-09-16
MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.
[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] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020257998A1
公开（公告）日：2020-12-30
Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.
[EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020006722A1
公开（公告）日：2020-01-09
A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
[EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
申请人：HOFFMANN LA ROCHE
公开号：WO2021234004A1
公开（公告）日：2021-11-25
The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.
