A Simultaneous Mixed-Effects Pharmacokinetic Model for Nefopam, N-desmethylnefopam, and Nefopam N-Oxide in Human Plasma and Urine.

BACKGROUND AND OBJECTIVE: Nefopam is a non-opioid, non-steroidal, central analgesic thought to act via multiple mechanisms including potent inhibition of serotonin-norepinephrine reuptake and modulation of voltage-sensitive calcium and sodium channels. There has been a resurgence in its use for postoperative pain and neuropathic pain. Dosing route-dependent metabolism and clinical effects have been described following intravenous and oral nefopam. N-desmethylnefopam and nefopam N-oxide are metabolites of clinical interest. We sought to develop a joint pharmacokinetic model to simultaneously describe the plasma and urinary pharmacokinetics of nefopam and the two metabolites following an oral pharmacological dose of [14C]-nefopam to healthy volunteers, and to estimate inter-individual variability in their pharmacokinetics. METHODS: Pharmacokinetic data for the parent and metabolites were analyzed simultaneously using NONMEM® (nonlinear mixed-effect modeling) v7.3. The modeling process evaluated, in part, one- and two-compartment linear pharmacokinetic models for nefopam and a single compartment for each of the two metabolites. Pathways for presystemic metabolism of both metabolites were explored. RESULTS: The final structural model simultaneously described the plasma and urinary pharmacokinetics of nefopam and the two metabolites. It consists of a central compartment for nefopam and for each of the two metabolites, as well as a peripheral compartment for the parent, and the associated urine compartments. The rapid formation and appearance of the N-oxide in plasma, characterized by concentrations that peak earlier than the parent, could be described by presystemic formation in the gastrointestinal tract. CONCLUSIONS: A descriptive, robust and predictive parent-metabolite model has been developed using a population mixed-effects approach to characterize the pharmacokinetics of nefopam and its metabolites simultaneously in healthy subjects following oral administration of nefopam. The model may be used for dose selection, analysis of sparse data, identification of intrinsic and extrinsic factors, and to model the clinical effects of each analyte.

Unravelling the binding mechanism and protein stability of human serum albumin while interacting with nefopam analogues: a biophysical and insilico approach.

In this study, molecular binding affinity was investigated for Nefopam analogues (NFs), a functionalized benzoxazocine, with human serum albumin (HSA), a major transport protein in the blood. Its binding affinity and concomitant changes in its conformation, binding site and simulations were also studied. Fluorescence data revealed that the fluorescence quenching of HSA upon binding of NFs analogues is based on a static mechanism. The three analogues of NFs binding constants (KA) are in the order of NF3 > NF2 > NF1 with values of 1.53 ± .057 × 104, 2.16 ± .071 × 104 and 3.6 ± .102 × 105 M-1, respectively. Concurrently, thermodynamic parameters indicate that the binding process was spontaneous, and the complexes were stabilized mostly by hydrophobic interactions, except for NF2 has one hydrogen bond stabilizes it along with hydrophobic interactions. Circular dichroism (CD) studies revealed that there is a decrease in α-helix with an increase in ß-sheets and random coils signifying partial unfolding of the protein upon binding of NFs, which might be due to the formation of NFs-HSA complexes. Further, molecular docking studies showed that NF1, NF2 and NF3 bound to subdomains IIIA, IB and IIA through hydrophobic interactions. However, NF1 have additionally formed a single hydrogen bond with LYS 413. Furthermore, molecular simulations unveiled that NFs binding was in support with the structural perturbation observed in CD, which is evident from the root mean square deviation and Rg fluctuations. We hope our insights will provide ample scope for engineering new drugs based on the resemblances with NFs for enhanced efficacy with HSA.

Nefopam pharmacokinetics in patients with end-stage renal disease.

BACKGROUND: Treatment of intense postoperative pain in patients with end-stage renal disease (ESRD) is a recurrent problem for anesthesiologists because of the risk of accumulation of numerous molecules and their metabolites. Nefopam is a potent analgesic metabolized by the liver and weakly eliminated intact in urine that may offer advantages for use in patients with ESRD because it lacks respiratory-depressive effects. However, the effects of renal failure on nefopam disposition have never been investigated. METHODS: We studied 12 ESRD patients (creatinine clearance < 20 mL/min, mean age 57 ± 13 years) having surgery under general anesthesia to create or repair an arteriovenous fistula. Postoperatively, after complete recovery from anesthesia, each patient received a single 20-mg dose of nefopam IV over 30 minutes. Nefopam and desmethyl-nefopam concentrations in plasma samples obtained over 48 hours were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameter values obtained were compared with those of 12 healthy 50- to 60-year-old volunteers who also received a single 20-mg nefopam infusion over 30 minutes using a population pharmacokinetic approach. RESULTS: Healthy volunteers and ESRD patients had comparable demographic characteristics. In comparison with those volunteers, ESRD patients had a lower volume of central compartment (115 and 53 L vs. 264 L for patients not yet hemodialyzed and on chronic hemodialysis, respectively; P < 0.001) and lower mean nefopam clearance (37.0 and 27.3 L/h vs. 52.9 L/h, P < 0.001), resulting in higher mean nefopam peak concentration (121 and 223 ng/mL vs. 61 ng/mL, P < 0.001). CONCLUSIONS: Nefopam distribution and elimination are altered in patients with ESRD, resulting in heightened exposure. To avoid too-high concentration peaks, it is suggested that the daily nefopam dose be reduced by 50%.

High-yielding synthesis of Nefopam analogues (functionalized benzoxazocines) by sequential one-pot cascade operations.

An efficient amine-/ruthenium-catalyzed three-step process for the synthesis of Nefopam analogues was achieved through combinations of cascade enamine amination/iso-aromatization/allylation and diene or enyne metathesis as key steps starting from functionalized Hagemann's esters. In this communication, we discovered the application of ruthenium-catalysis on olefins containing free amines without in situ formation of salts.

Specific and sensitive analysis of nefopam and its main metabolite desmethyl-nefopam in human plasma by liquid chromatography-ion trap tandem mass spectrometry.

A specific and sensitive liquid chromatography-tandem mass spectrometric (LC-MS-MS) method using an ion trap spectrometer was developed for quantitation of nefopam and desmethyl-nefopam in human plasma. Nefopam, desmethyl-nefopam and the internal standard (ethyl loflazepate) were extracted in a single step with diethyl ether from 1 mL of alkalinized plasma. The mobile phase consisted of acetonitrile with 0.1% formic acid (50:50, v:v). It was delivered at a flow-rate of 0.3 mL/min. The effluent was monitored by MS-MS in positive-ion mode. Ionisation was performed using an electrospray ion source operating at 200 degrees C. Nefopam and desmethyl-nefopam were identified and quantified in full scan MS-MS mode using a homemade MS-MS library. Calibration curves were linear over the concentration range of 0.78-100 ng/mL with determination coefficients >0.996. This method was fast (total run time<6 min), accurate (bias<12.5%), and reproducible (intra- and inter-assay precision<17.5%) with a quantitation limit of 0.78 ng/mL. The high specificity and sensitivity achieved by this method allowed the determination of nefopam and desmethyl-nefopam plasma levels in patients following either intermittent or continuous intravenous administration of nefopam.

Comparative pharmacokinetics and pharmacodynamics of intravenous and oral nefopam in healthy volunteers.

To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double-blind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36+/-0.13. The AUCoral/AUCiv ratio of nefopam+desmethyl-nefopam was 0.62+/-0.23. The half-life of nefopam was similar whether administered orally (5.1+/-1.3 hr) or intravenously (5.1+/-0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6+/-3.0 versus 5.1+/-1.3 hr, P<10(-4) and intravenously: 15.0+/-2.4 versus 5.1+/-0.6 hr, P<10(-4)). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug-naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC0-->24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90+/-142 versus 35+/-84 (P=0.27) and 66+/-74 versus 46+/-54 mm x hr (P=0.36), respectively. The AUC0-->24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68+/-65 versus 27+/-30 (P=0.005) and 54+/-63 versus 28+/-48 mm x hr (P=0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.

Effect of route of administration on the pharmacokinetic behavior of enantiomers of nefopam and desmethylnefopam.

Nefopam hydrochloride is a non-narcotic analgesic used parenterally and orally as a racemic mixture for the relief of postoperative pain. However, no information is presently available on the oral kinetics of (+) and (-) nefopam in humans. Also, nefopam is metabolized by N-demethylation but it is not known whether the desmethylnefopam enantiomers (DES1 and DES2) are present in plasma following intravenous (I.V.) or oral administration of parent drug. To address these issues, 24 healthy white male subjects received two treatments using a double-blind, placebo-controlled crossover design: oral administration of 20 mg nefopam hydrochloride solution or a placebo solution on a sugar cube, simultaneously with a continuous infusion of 20 mg nefopam hydrochloride or placebo infusion. A chiral assay using LC-MS was developed for the simultaneous determination of both enantiomers of the parent drug and its metabolite in plasma and urine. Following I.V. administration, the kinetics of (+) and (-) nefopam could be fitted to a bi-exponential equation but exhibited no stereoselectivity. Both enantiomers had large clearances (53.7 and 57.5 L/hr) and volumes of distribution (390 and 381 L) and half-lives around 5 hours. Following oral administration, (+) and (-) nefopam were rapidly absorbed with bioavailabilities of 44% and 42%, respectively, probably due to a first-pass effect. After I.V. administration, the enantiomers of desmethylnefopam exhibited lower concentrations and longer half-lives (20.0 h for DES1 and 25.3 h for DES2) relative to nefopam enantiomers. Following oral administration, desmethylnefopam enantiomers' plasma concentrations peaked earlier and higher than after I.V. administration (P < 0.05). Following I.V. and oral administration, desmethylnefopam enantiomers showed stereoselectivity in AUC and Cmax values. Urinary excretion of parent and metabolite enantiomers was less than 5% of dose. This study shows that desmethylnefopam enantiomers can contribute to the analgesic effect of racemic nefopam only when it is administered orally.

Solid-state stereochemistry and activity of 3-methylnefopam diastereomers: manipulation of eight-membered ring conformations in analogues of the non-narcotic analgesic drug.

The solid-state structures of (+/-)-(1R,3S,5S)/(1S,3R,5R)- and (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-methylnefopam hydrochloride, epimeric 3-methyl derivatives of the non-narcotic analgesic drug, were determined by single-crystal X-ray diffraction analyses. (+/-)-(1R,3S,5S)/(1S,3R,5S)-3-Methylnefopam hydrochloride gave crystals belonging to the monoclinic space group P2(1)/c, and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) A, beta = 93.06 degrees, V = 3234(2) A3, Z = 8, R(F = 0.070, and Rw(F) = 0.053. (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-Methylnefopam hydrochloride gave chiral crystals belonging to the orthorhombic space group P2(1)2(1)2(1), and at 92 K, a = 9.261(2), b = 10.280(2), c = 16.668(4) A, V = 1587(1) A3, Z = 4, R(F) = 0.034, and Rw(F) = 0.035. The two molecules in the asymmetric unit of the (1R,3S,5S)/(1S,3R,5R)-racemic modification had twist-chair-(flattened chair) [TCfC] conformational geometries for the eight-membered ring. Both molecules are virtually identical as shown by a root mean squares fit of 0.077 A in the superimposition of all nonhydrogen atoms in both molecules. The (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-epimers were found in the same boat-(flattened chair) [BfC] conformation previously noted for crystalline nefopam hydrochloride. The TCfC and BfC eight-membered ring conformations of the two 3-methylnefopam diastereomers differ in the -N+H(CH3)CH2CH-fragment chair or boat arrangement vis-a-vis the adjacent flattened region. In both 3-methyl diastereomers, the C(3)-methyl group was disposed in an equatorial orientation, the phenyl group resided in an exo-position, and the -OCH(Ph)-o-C6H4- fragment occupied the flattened region of the eight-membered ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Solution- and solid-state structures of N-desmethylnefopam hydrochloride, a metabolite of the analgesic drug.

The solid-state structure of (+/-)-N-desmethylnefopam hydrochloride (1), a metabolite of the analgesic drug, was determined by single-crystal X-ray diffraction analysis. Compound 1 gave crystalline prisms belonging to the orthorhombic Pcab space group, and at ambient temperature (293 K), a = 9.939(2), b = 14.479(1), c = 20.148(3) A, V = 2899.5(8) A3, Z = 8, R(F) = 0.045, and Rw(F) = 0.025. The benzoxazocine ring of crystalline 1 is twisted into the boat-flattened (chair) [BfC] conformation, the phenyl ring resides in a relatively sterically unhindered exo-type ring position, whereas the O atom and NCH2Ar occupy sterically hindered positions between "boat" and "chair" regions. Dissolution of BfC crystalline 1 in CD2Cl2 solvent affords a dynamic conformational equilibrium (involving the putative twist-chair-flattened (chair) conformer) as shown by line broadening and weighted time-averaged vicinal coupling constants [-OCH2CH2N- segment] in the 1H NMR spectrum. The solution-state weighted time-averaged 50(1) degrees O-CH2-CH2-N dihedral angle, calculated by the R-ratio method, shows that the BfC conformation is the major contributor to time-averaged structure.