The metabolism of hydromorphone is mainly hepatic and it is represented by the generation of hydromorphone-3-glucuronide through glucuronidation reactions. This primary metabolic pathway is done by the activity of the UDP-glucuronosyltransferase-2B7. The first-pass hepatic metabolism is so large that it represents 62% of the initial administered dose. On the other hand, hydromorphone is also characterized by the presence of minor metabolic pathways such as the CYP3A4- and CYP2C9-driven generation of norhydromorphone.
来源:DrugBank
代谢
代谢主要是通过肝脏，代谢物和未改变的药物通过尿液排出。
Metabolism is primarily via the liver, with metabolites and unchanged drug excreted in the urine.
Hydromorphone is metabolized primarily in the liver where it undergoes conjugation with glucuronic acid and is excreted principally in the urine as the glucuronide conjugate. /Hydromorphone hydrochloride/
Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency.
Morphine is one of several opioids used to treat chronic pain. Because of its high abuse potential, urine drug tests can confirm "consistency with prescribed medications." Hydromorphone is a recently described minor metabolite of morphine, but few data exist on the characteristics of this metabolic pathway or the relationship of morphine and hydromorphone between and within subjects. Part I of this retrospective study shows that formation of hydromorphone from morphine is concentration-dependent and possibly saturated at high concentrations of morphine. In addition, the percentage of ultra-rapid metabolizers and poor metabolizers can be determined using the lower asymptote of a sigmoidal mathematical fit and are estimated to be 0.63 and 4.0%, respectively. Expected limits of morphine and hydromorphone (as a result of morphine metabolism) concentrations in the urine were established. Part II of this study used the metabolic ratio (hydromorphone-morphine) to determine the inter-patient and intra-patient variability in morphine metabolism to hydromorphone. Metabolic ratio values varied over a large range; 25-fold and 7-fold, respectively. The expected limits established in this study can assist in assessing the cause for possible variances in metabolism, such as drug interactions. The wide variability between and within subjects may explain unpredictable, adverse effects.
IDENTIFICATION AND USE: Hydromorphone forms as crystals from ethanol. Hydromorphone is analgesic drug and a Schedule II controlled substance. HUMAN EXPOSURE AND TOXICITY: Acute overdosage produces signs of opioid toxicity: circulatory and CNS depression, lethargy, coma, respiratory depression, and decreased GI motility with ileus. Apnea, hypotension, bradycardia, noncardiogenic pulmonary edema, seizures, dysrhythmias, and death may occur with severe poisoning. Pruritus may occur and persist during epidural hydromorphone infusion. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Parenteral hydromorphone has few neuroexcitatory symptoms until H3G accumulates past a neurotoxic threshold, such as might occur with increasing dose or duration, which, when exceeded, causes neuroexcitatory symptoms to manifest. In a study of 33 deaths related to hydromorphone, fatalities due to hydromorphone occurred at 51 ng/mL and greater; however, tolerant users of this drug, as seen in the deaths attributed to natural causes, may achieve incidental concentrations that would otherwise be considered fatal. Dosage of hydromorphone hydrochloride should be reduced in patients with renal or hepatic impairment based on the degree of impairment. Hydromorphone hydrochloride extended-release tablets should not be administered to patients with any underlying condition that can result in narrowing of the GI tract. ANIMAL STUDIES: When administered intraperitoneally, hydromorphone caused a significant decrease in hepatic hepatocellular glutathione (GSH) concentrations in male mice. In mice after intrathecal (i.t.) administration hydromorphone produced both hypoglycemic and behavioral effects. Hydromorphone (0.1, 0.3, and 0.6 mg/kg) and an equivalent volume of saline (0.9% NaCl) solution (control treatment) were administered intramuscularly to kestrels in a masked randomized complete crossover study design. Hydromorphone at 0.6 mg/kg significantly increased the thermal foot withdrawal threshold, compared with the response after administration of saline solution, and hydromorphone at 0.1, 0.3, and 0.6 mg/kg significantly increased withdrawal responses compared with baseline values. Appreciable sedation was detected in 4 birds when administered 0.6 mg of hydromorphone/kg. Hydromorphone can be administered to dogs following orthopedic surgery without a clinically important risk of vomiting or regurgitation.
Hydromorphone is a narcotic analgesic; its principal therapeutic effect is relief of pain. Hydromorphone interacts predominantly with the opioid mu-receptors. These mu-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. In clinical settings, Hydromorphone exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Hydromorphone also binds with kappa-receptors which are thought to mediate spinal analgesia, miosis and sedation.
The immediate release version of hydromorphone reaches its peak concentration after 30-60 minutes while the extended-release version reaches the peak concentration after 9 hours. When administered orally, hydromorphone is absorbed mainly in the upper small intestine with a bioavailability of 60% due to intensive first-pass metabolism. In the controlled-release version of hydromorphone, the absorption follows a biphasic pharmacokinetic profile. However, even though there are clear distinctions in the absorption pathway of hydromorphone, the AUC of both versions is reported to be of 34 ng.h/ml which indicates an equivalence. The parenteral administration of hydromorphone, which is the most common pathway, presents an almost immediate absorption as observed by the presence of peak plasma concentration almost immediately. This peak plasma concentration declines rapidly due to fast redistribution into liver, spleen, kidney and skeletal muscle. In the parenteral route, the pharmacokinetic profile is log-linear and dose-dependent and to present a higher bioavailability of 78%. Other administration routes such as rectal, nasal, intraspinal and transdermal present lower bioavailability and changes in their pharmacokinetic profile.
The main elimination route of hydromorphone is through the urine in the form of the main metabolite hydromorphone-3-glucuronide. The elimination of the parent compound represents 7% of the urine elimination and 1% of the fecal elimination.
来源:DrugBank
吸收、分配和排泄
分布容积
氢吗啡酮的分布容积据报道为4 L/kg。
The volume of distribution of hydromorphone is reported to be of 4 L/kg.
来源:DrugBank
吸收、分配和排泄
清除
氢吗啡的平均血浆清除率为105.7毫升/分钟。系统清除率据报道为1.96升/分钟。
The mean plasma clearance of hydromorphone is reported to be of 105.7 ml/min. The systemic clearance is reported to be of 1.96 L/min.
Hydromorphone hydrochloride is rapidly but incompletely absorbed from the gastrointestinal tract after oral doses; peak plasma concentrations occur within 0.5 to 1 hour. Oral bioavailability is about 50% as it undergoes extensive first-pass metabolism. Hydromorphone is about 8 to 19% bound to plasma proteins. A plasma elimination half-life of about 2.5 hours has been reported after oral or intravenous doses. Hydromorphone appears to be widely distributed in the tissues; it crosses the placenta and is distributed into breast milk. It is extensively metabolized by glucuronidation in the liver and excreted in the urine mainly as conjugated hydromorphone, dihydroisomorphine, and dihydromorphine. /Hydromorphone hydrochloride/
[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] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
申请人：MERCK SHARP & DOHME
公开号：WO2011149801A1
公开（公告）日：2011-12-01
The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
[EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
申请人：UNIV EMORY
公开号：WO2013181135A1
公开（公告）日：2013-12-05
The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.
Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
申请人：D'Sidocky Neil R.
公开号：US20080242694A1
公开（公告）日：2008-10-02
Provided herein are Heterocyclic Compounds having the following structure:
wherein R
1
, R
2
, X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.
A pharmaceutically active inventive compound comprises two independently active analgesic moieties covalently conjoined through a physiologically labile linker. A preferred embodiment comprises an opioid, such as morphine, covalently linked to at least one analgesic compound selected from the group consisting of an opioid or a non-opioid compound through a physiologically labile linker. Suitable covalent linkers are covalently bonded to the two independently active analgesic compounds through one or more lactone, lactam, or sulfonamido linkages. Suitable linkers include endogenous carboxylate, amido, and sulfonamido moieties, and exogenous moieties that form the aforementioned lactone, lactam or sulfonamido linkages.
