Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine also undergoes N-demethylation to normeperidine, which then undergoes hydrolysis and partial conjugation. Normeperidine is about half as potent as meperidine, but it has twice the CNS stimulation effects.
Meperidine is metabolized principally in the liver. The drug is biotransformed mainly by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine may also undergo N-demethylation to normeperidine followed by hydrolysis and partial conjugation. Other metabolites also have been identified, but only normeperidine has been detected in blood or plasma. When urine pH is uncontrolled, approximately 5-30% of a dose of meperidine is excreted in urine as the N-demethylated derivative and about 5% is excreted unchanged; however, the relative proportion of the drug excreted in urine unchanged and as metabolites is pH dependent. Meperidine and normeperidine are found in acid urine whereas meperidinic and normeperidinic acids in the free and conjugated form are present in alkaline urine. Excretion of the unchanged drug and normeperidine is enhanced by acidifying the urine. Normeperidine is pharmacologically active, reportedly exhibiting about half the analgesic potency of meperidine but twice the CNS stimulant (e.g., seizure-inducing) potency. Various toxic effects secondary to CNS stimulation (e.g., seizures, agitation, irritability, nervousness, tremors, twitches, myoclonus) have been attributed to accumulation of this metabolite. The elimination half-life of normeperidine is substantially longer than that of meperidine, reportedly ranging from 8-21 hours, and may be prolonged (e.g., to longer than 30 hours) in patients with renal impairment. Accumulation of this metabolite may occur with repeated, high doses of the drug and in patients with renal or hepatic impairment.
Meperidine (Demerol) is a mu- and kappa-opiate receptor agonist used for moderate to severe pain. Overdose can result in respiratory depression, hypotension and coma, while accumulation of its toxic metabolite, normeperidine, can cause delirium and seizures. Little data exist examining the inter- and intrasubject variability of the normeperidine-to-meperidine metabolic ratio (MR) in urine. This retrospective data analysis examined meperidine and normeperidine urine concentrations collected from chronic pain patients. In 98 subjects with multiple visits, the geometric mean urinary MR = 6.1 (coefficient of variation, %CV = 68%). From single specimens obtained from 799 subjects, the geometric mean urinary MR = 6.2 (%CV = 212%). The urinary MR increased in young subjects compared with elderly (P = 0.004) and middle-aged subjects (P = 0.01). A 27% difference was found between the male and female urinary MR (male geometric mean MR = 5.1, female geometric mean MR = 7.0, P = 0.02). Intersubject variability in meperidine metabolism was 3-fold greater than intrasubject variability. A significant difference in the urinary MR was found between males and females. The substantial variability in meperidine metabolism and the serious side effects of its metabolite normeperidine require greater vigilance in patient medication monitoring.
Human liver carboxylesterases catalyze the hydrolysis of apolar drug or xenobiotic esters into more soluble acid and alcohol products for elimination. Two carboxylesterases, hCE-1 and hCE-2, have been purified and characterized with respect to their role in cocaine and heroin hydrolysis. The binding of meperidine (Demerol) and propoxyphene (Darvon) was examined in a competitive binding, spectrophotometric assay. The hCE-1 and hCE-2 bound both drugs, with Ki values in the 0.4- to 1.3-mM range. Meperidine was hydrolyzed to meperidinic acid and ethanol by hCE-1 but not hCE-2. The Km of hCE-1 for meperidine was 1.9 mM and the kcat (catalytic rate constant) was 0.67 min-1. Hydrolysis of meperidine by hCE-1 was consistent with its specificity for hydrolysis of esters containing simple aliphatic alcohol substituents. Hence, hCE-1 in human liver microsomes may play an important role in meperidine elimination. Propoxyphene was not hydrolyzed by hCE-1 or hCE-2. This observation is consistent with the absence of a major hydrolytic pathway for propoxyphene metabolism in humans.
IDENTIFICATION AND USE: Meperidine is a solid. Meperidine is a strong analgesic used in the relief of moderate to severe pain. The drug has been used to relieve the pain of myocardial infarction. Meperidine also is used parenterally for preoperative sedation, as a supplement to anesthesia, and to provide analgesia during labor. HUMAN STUDIES: Meperidine is a mu- and kappa-opiate receptor agonist with approximately 20-25% the potency of morphine. Receptors for opiate analgesics are found in high concentrations in the limbic system, spinal cord, thalamus, hypothalamus, striatum, and midbrain. They are also found in tissues such as the gastrointestinal tract, urinary track, and in other smooth muscle. Meperidine is different from other opioids because its active metabolite, normeperidine, is neurotoxic. The lethal meperidine blood concentration is 1-3 mg/dL. Common side effects include nausea, vomiting and hypotension. Meperidine can produce further hypotension in patients who have blood loss due to trauma. In high doses, it has been associated with seizure. Obstetric analgesia in the form of meperidine to mothers during delivery has adverse effects on some aspects of the behavior of their newborn infants. ANIMAL STUDIES: In mice a reversible opacity of the front of the lens has been observed to develop acutely after systematic administration of meperidine, because of reduced blinking, exposing the eye to evaporation and causing dehydration of the lens. Meperidine is reported to inhibit the release of gonadotropins in animals. Prolonged administration of up to 6 times the recommended therapeutic dose to dogs produces slight anorexia and loss of weight. Doses of 100 mg or more produce excitement and clonic convulsions, which can be controlled by barbiturates, in cats. Following an im dose of 10 mg/kg meperidine, reduction in heart rate and drop in the systemic arterial pressure occur in dogs. Generally, the fall in blood pressure is moderate, and occurs 10-20 minutes after im injection, with return to control level in 30 minutes. Subcutaneous doses in excess of 20-30 mg/kg meperidine can produce excitement and clonic convulsions in cats. The chronic epidural administration of pethidine in rabbits induces moderate to severe histological changes on the spinal cord.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
毒性总结
度冷丁主要是一种激活 kappa-阿片受体的激动剂，并且具有局部麻醉效果。度冷丁对 kappa-受体的亲和力比吗啡更强。阿片受体与 G-蛋白受体偶联，并通过激活效应蛋白的 G-蛋白作为突触传递的正负调节因子。阿片类药物的结合刺激了 G-蛋白复合物上 GTP 与 GDP 的交换。由于效应系统是位于质膜内表面的腺苷酸环化酶和 cAMP，阿片类药物通过抑制腺苷酸环化酶来降低细胞内 cAMP。随后，痛觉神经递质如 P 物质、GABA、多巴胺、乙酰胆碱和去甲肾上腺素的释放被抑制。阿片类药物还抑制血管加压素、生长抑素、胰岛素和胰高血糖素的释放。阿片类药物关闭 N-型电压门控钙通道（OP2-受体激动剂）并打开钙依赖性内向整流钾通道（OP3 和 OP1 受体激动剂）。这导致超极化并减少神经元兴奋性。
Meperidine is primarily a kappa-opiate receptor agonist and also has local anesthetic effects. Meperidine has more affinity for the kappa-receptor than morphine. 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. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
Therapy with meperidine has not been linked to serum enzyme elevations. There have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to meperidine.
References on the safety and potential hepatotoxicity of meperidine are given in the Overview section of the Opioids.
Drug Class: Opioids
The oral bioavailability of meperidine in patients with normal hepatic function is 50-60% due to extensive first-pass metabolism. Bioavailability increases to 80-90% in patients with hepatic impairment (e.g. liver cirrhosis). Meperidine is less than half as effective when administered orally compared to parenteral administration. One study reported that 80-85% of the drug administered intramuscularly was absorbed within 6 hours of intragluteal injection in health adults; however, inter-individual variation and patient-specific variable appear to cause considerable variations in absorption upon IM injection.
Excreted in the urine. The proportion of drug that is excreted unchanged or as metabolites is dependent on pH. When urine pH is uncontrolled, 5-30% of the meperidine dose is excreted as normeperidine and approximately 5% is excreted unchanged. Meperidine and normeperidine are found in acidic urine, while the free and conjugated forms of meperidinic and normperidinic acids are found in alkaline urine.
Following oral administration, meperidine undergoes extensive metabolism on first pass through the liver, with approximately 50-60% of a dose reaching systemic circulation unchanged. In patients with hepatic impairment (e.g., liver cirrhosis), oral bioavailability of meperidine increases to approximately 80-90%. Meperidine is less than one-half as effective when given orally as when given parenterally. Approximately 80-85% of an IM dose of the drug reportedly was absorbed within 6 hours after intragluteal injection in healthy adults in one study; however, absorption from the IM injection site appears to show considerable interindividual variation and may depend on the site of injection, dose, and patient-specific variables. Meperidine appears to have a more rapid onset and shorter duration of action than does morphine. Following oral administration of meperidine, peak analgesia occurs within one hour and gradually declines over 2-4 hours. Peak analgesia occurs about 40-60 minutes after subcutaneous administration and 30-50 minutes after IM administration. Analgesia may be maintained for 2-4 hours following subcutaneous or IM administration.
Meperidine is approximately 60-80% bound to plasma proteins, principally albumin and alpha1-acid glycoprotein (alpha1-AGP). There is some evidence that the ratio of bound to free drug is correlated with plasma alpha1-AGP concentrations. In patients with cirrhosis or active viral hepatitis, the extent of protein binding does not appear to be affected.
[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.
The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.
[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.
本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
[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.
