Multiplex detection of 14 fentanyl analogues and U-47700 in biological samples: Application to a panel of French hospitalized patients.

Synthetic opioids (SO) associated with the recent alarming increase of deaths and intoxications in United States of America and Europe are not detected by the usual first-line opiates drug screening assays. We developed a liquid chromatography tandem mass spectrometry analytical method for the multiplex detection of 14 fentanyl analogues (2-furanylfentanyl, 4-ANPP, 4-methoxybutyrylfentanyl, acrylfentanyl, alfentanil, carfentanil, despropionyl-2-fluorofentanyl, fentanyl, methoxyacetylfentanyl, norfentanyl, ocfentanil, remifentanil, sufentanil and valerylfentanyl) and U-47700 in whole blood and urine samples. The method was validated according to the requirements of ISO 15189. A simple and fast liquid-liquid extraction (LLE) with De-Tox Tube-A was performed leading to better recovery of molecules in urine than in blood samples. Depending on the compound, the limits of detection (LODs) ranged from 0.01 to 0.10 ng/mL and from 0.02 to 0.05 ng/mL in whole blood and urine, respectively. Calibration curves were linear in the range 0.5-50.0 ng/mL and the limit of quantification (LOQ) ranged from 0.10 to 0.40 ng/mL in blood. Internal quality controls at 1 and 40 ng/mL showed intra-day and between-day precision and accuracy bias below 10% in urine and 15% in blood. The method was applied to the screening of 211 urine samples from patients admitted in emergency or addiction departments. The presence of legal fentanyl analogues in 5 urine samples was justified by their therapeutic use as analgesics. Only one patient was concerned by fentanyl misuse and addiction whereas no illegal SO was detected. This study is not in favor of a huge misuse of SO in the Lorraine region.

Effects of different sufentanil target concentrations on the MACBAR of sevoflurane in patients with carbon dioxide pneumoperitoneum stimulus.

BACKGROUND: This study aims to observe the effects of different target controlled plasma sufentanil concentrations on the minimum alveolar concentration (MAC) of sevoflurane for blocking adrenergic response (BAR) in patients undergoing laparoscopic cholecystectomy with carbon dioxide pneumoperitoneum stimulation. METHODS: Eighty-five patients undergoing laparoscopic cholecystectomy, aged 30-65 years, with American Society of Anesthesiologists physical status I-II, were enrolled in this study. All the patients were randomly divided into 5 groups (S0, S1, S2, S3, S4) with different sufentanil plasma target concentration (0.0, 0.1, 0.3, 0.5, 0.7 ng ml- 1). Anesthesia was induced by inhalation of 8% sevoflurane in 100% oxygen, and 0.6 mg kg- 1 of rocuronium was intravenously injected to facilitate the insertion of a laryngeal mask airway. The end-tidal sevoflurane concentration and sufentanil plasma target concentration were adjusted according to respective preset value in each group. The hemodynamic response to pneumoperitoneum stimulus was observed after the end-tidal sevoflurane concentration had been maintained stable at least for 15 min. The MACBAR of sevoflurane was measured by a sequential method. Meanwhile, epinephrine (E) and norepinephrine (NE) concentrations in the blood were also determined before and after pneumoperitoneum stimulus in each group. RESULTS: When the method of independent paired reversals was used, the MACBAR of sevoflurane in groups S0, S1, S2, S3, S4 was 5.333% (confidence interval [CI] 95%: 5.197-5.469%), 4.533% (95% CI: 4.451-4.616%), 2.861% (95% CI: 2.752-2.981%), 2.233% (95% CI: 2.142-2.324%) and 2.139% (95% CI: 2.057-2.219%), respectively. Meanwhile, when the isotonic regression analysis was used, the MACBAR of sevoflurane in groups S0, S1, S2, S3, S4 was 5.329% (95% CI: 5.321-5.343%), 4.557% (95% CI: 4.552-4.568%), 2.900% (95% CI: 2.894-2.911%), 2.216% (95% CI: 2.173-2.223%) and 2.171% (95% CI: 2.165-2.183%), respectively. The MACBAR was not significantly different between groups S3 and S4 when using 0.5 and 0.7 ng ml- 1 of sufentanil plasma target concentrations. No significant difference was found in the change of E or NE concentration between before and after pneumoperitoneum stimulation in each group. CONCLUSIONS: The MACBAR of sevoflurane can be decreased with increasing sufentanil plasma target concentrations. A ceiling effect of the decrease occurred at a sufentanil plasma target concentration of 0.5 ng ml- 1. When the sympathetic adrenergic response was inhibited in half of the patients to pneumoperitoneum stimulation in each group, the changes of E and NE concentrations showed no significant differences. TRIAL REGISTRATION: The study was registered at http://www.chictr.org.cn ( ChiCTR1800015819 , 23, April, 2018).

Effect of the Combination of Ketorolac and Bupivacaine on Transversus Abdominis Plane Block for Postoperative Analgesia After Gynecological Laparoscopic Surgery.

BACKGROUND This study assessed the additional benefits of bupivacaine when combined with ketorolac for transversus abdominis plane (TAP) block after gynecological laparoscopic surgery. MATERIAL AND METHODS This randomized, observer-blind trial recruited 153 patients who underwent gynecological laparoscopic surgery. Patients were randomly assigned to receive bupivacaine combined with ketorolac 15 mg/side for TAP block (TK group), bupivacaine for TAP block and 30 mg postoperative intravenous ketorolac (T group), or 30 mg postoperative intravenous ketorolac alone (C group). The primary endpoints included consumption of sufentanil for 24 h postoperatively, actual press times of the patient-controlled analgesia (PCA) pump, and effective press times of the PCA pump, whereas the secondary endpoints included numerical rating scale (NRS) pain scores at rest and during activity, satisfaction with analgesia, episodes of nausea and vomiting and length of hospital stay. RESULTS Sufentanil consumption, actual press times of the PCA pump, and effective press times of the PCA pump were lower in the TK and T groups than in the C group. NRS scores at rest and during activity at 1, 2, 4, 6, and 24 hours were significantly lower in the TK and T groups than in the C group. The TK and T groups showed greater satisfaction with analgesia than the C group, while the TK group showed greater overall satisfaction than the C group. Lengths of stay, rates of nausea and vomiting, and venting times did not differ significantly among the three groups. CONCLUSIONS Combined ketorolac and bupivacaine as TAP block improved the effectiveness of analgesia without increasing adverse events. Trial registration number: ChiCTR1900022577.

Establishment and Its Application of UPLC-MS/MS Method for 20 Fentanyl-related Substances in Blood.

ABSTRACT: Objective To establish an ultra-high performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS） rapid determination method for simultaneous analysis of 20 fentanyl-related substances in blood. Methods With fentanyl-D5 as an internal standard, the blood was extracted by liquid-liquid extraction （LLE）, then separated with an ACQUITY UPLC HSS T3 chromatographic column, and finally 20 fentanyl-related substances were simultaneously analyzed with multiple reaction monitoring （MRM） mode. Results The limits of detection （LOD） of all compounds were 0.02-0.03 ng/mL, and the limits of quantitation （LOQ） were 0.05-0.2 ng/mL. Within the mass concentration range of 0.05-40 ng/mL, 20 fentanyl-related substances had a good linear relationship, and correlation coefficients were larger than 0.99. The accuracy of the method was 87.69%-114.68% and the extraction recovery rate was 85.35%-101.80%, and no significant matrix effect was observed. The established method was successfully applied to the detection of sufentanil in rat blood after sufentanil was injected. Sufentanil could still be detected in blood of rats 10 h after sufentanil injection. Conclusion The established method has the advantages of simple pretreatment, high sensitivity and good selectivity, and can be used for the determination of fentanyl-related substances in forensic toxicology analysis.

Establishment and Its Application of UPLC-MS/MS Method for 20 Fentanyl-related Substances in Blood / 法医学杂志

Objective To establish an ultra-high performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS） rapid determination method for simultaneous analysis of 20 fentanyl-related substances in blood. Methods With fentanyl-D5 as an internal standard, the blood was extracted by liquid-liquid extraction （LLE）, then separated with an ACQUITY UPLC HSS T3 chromatographic column, and finally 20 fentanyl-related substances were simultaneously analyzed with multiple reaction monitoring （MRM） mode. Results The limits of detection （LOD） of all compounds were 0.02-0.03 ng/mL, and the limits of quantitation （LOQ） were 0.05-0.2 ng/mL. Within the mass concentration range of 0.05-40 ng/mL, 20 fentanyl-related substances had a good linear relationship, and correlation coefficients were larger than 0.99. The accuracy of the method was 87.69%-114.68% and the extraction recovery rate was 85.35%-101.80%, and no significant matrix effect was observed. The established method was successfully applied to the detection of sufentanil in rat blood after sufentanil was injected. Sufentanil could still be detected in blood of rats 10 h after sufentanil injection. Conclusion The established method has the advantages of simple pretreatment, high sensitivity and good selectivity, and can be used for the determination of fentanyl-related substances in forensic toxicology analysis.

Potentially clinically relevant concentrations of Cefazolin, Midazolam, Propofol, and Sufentanil in auto-transfused blood in congenital cardiac surgery.

BACKGROUND: Use of donor blood in congenital cardiac surgery increases the risk for post-operative morbidity and mortality. To reduce the need for allogenic blood transfusion a technique for peri-operative mechanical red cell salvage is applied. Blood from the operation site is collected in a reservoir, processed, passed through a lipophilic filter and returned to the patient. Influence of this cellsaver system on coagulation, fibrinolysis and inflammatory markers is known. To our knowledge no studies have been performed on the effects of autotransfusion on drug concentrations. A clinically relevant drug dose could potentially be returned to the patient through the auto-transfused blood, leading to unwanted drug reactions post-operatively. We aimed to measure drug concentrations in blood salvaged from the operation site and in the auto-transfused blood to determine if a clinically relevant drug dose is returned to the patient. METHODS: The study was performed at the Department of Cardiothoracic Surgery of a tertiary university hospital. Blood samples were taken from the reservoir, after processing before the lipophilic filter, the auto-transfused blood, and the waste fluid. Samples were stored at - 80 C and drug concentration for sufentanil, propofol, midazolam and cefazolin were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drug concentrations measured in the reservoir and the auto-transfused blood were compared and the relative reduction was calculated for each patient. RESULTS: Blood samples were taken from 18 cellsaver runs in 18 patients, age 0-13 years. Drug concentrations in the reservoir were comparable to concomitant concentrations in the patient. For sufentanil 34% (median, IQR 27-50) of drug concentration was retained from the reservoir in the auto-transfused blood, for midazolam 6% (median, IQR 4-10), for cefazolin 5% (median, IQR 2-6) and for propofol 0% (median, IQR 0-0) respectively. CONCLUSION: Depending on the drug, up to 34% of the drug concentration salvaged from the operation site is returned to the patient through autotransfusion, potentially causing unwanted drug reactions post-operatively. Additionally, influence of a cellsaver system should be considered in pharmacological research during and after congenital cardiac surgery and could result in dose adjustments in the postoperative phase. TRIAL REGISTRATION: Registration at the Dutch Trial Registry ( NTR3579 ) at August 14 2012.

CYP3A4 gene polymorphism is correlated with individual consumption of sufentanil.

BACKGROUND: Pain is one of the major adverse clinical outcomes of cesarean section (CS). In the past few years, researchers and physicians have been optimizing post-operative analgesic modalities, but the results are still undesirable for the parturient. The cytochrome P-450 3A4 (CYP3A4) gene has been reported to contribute significantly to human liver microsomal oxidation of sufentanil and alfentanil. METHODS: We detected the frequency of CYP3A4 mutant allele, which is associated with the metabolism of diverse drugs, including opioids used for anesthesia. We then investigated the correlation between sufentanil (an opioid analgesic) consumption and CYP3A4 genetic polymorphism. RESULTS: We found the frequency of the CYP3A4∗1G (the mutant form of CYP3A) variant allele to be 0.279 in 71 parturients undergoing cesarean section and 137 age-matched parturients with vaginal delivery. Interestingly, the parturients with homozygous CYP3A4∗1G showed less sufentanil consumption compared with those having the wild-type genotype. CONCLUSION: In summary, we found a correlation between CYP3A4 genetic polymorphism and sufentanil consumption. This might be helpful for optimizing the anesthesia strategies and reducing their side effects.

Pharmacokinetics of sufentanil during long-term infusion in critically ill pediatric patients.

The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed-effects modeling was performed using NONMEM. A 2-compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 5.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady-state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70-kg adult patient, µg/h) × (body weight/70 kg)(0.75). Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates.

Effect of aortic root infusion of sufentanil on ischemia-reperfusion injury in patients undergoing mitral valve replacement.

OBJECTIVE: This study investigated the effects of aortic root infusion of sufentanil on myocardial ischemia/reperfusion injury in patients undergoing elective mitral valve replacement (MVR) with cardiopulmonary bypass (CPB). DESIGN: A prospective, randomized, clinical study. SETTING: A university-affiliated teaching hospital. PARTICIPANTS: Fifty-three adult patients undergoing elective MVR with CPB. INTERVENTIONS: Bolus infusions of sufentanil (0.2 µg/kg, n = 24) or normal saline (n = 29) were administered through the aortic root cardioplegia perfusion catheter 5 minutes before aortic unclamping. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of CK-MB and cTnI and variables including heart rate, mean arterial pressure, central venous pressure, cardiac output, stroke volume, duration of mechanical ventilation, length of ICU stay, length of hospital stay, and 24-hour postoperative inotropic scores were recorded. Plasma concentrations of CK-MB and cTnI were significantly lower 4 and 8 hours after aortic unclamping in the sufentanil postconditioning group compared to control (p<0.05). Inotropic drug use, duration of mechanical ventilation, and length of ICU and hospital stays were reduced significantly in the sufentanil postconditioning group compared to control (p< 0.05). CONCLUSIONS: The present study demonstrated that sufentanil can attenuate myocardial ischemia-reperfusion injury in patients undergoing elective MVR with CPB.

Pharmacokinetics of sufentanil administered with 0.2% ropivacaine as a continuous epidural infusion for postoperative pain relief in infants.

BACKGROUND AND OBJECTIVES: Our objective was to assess plasma sufentanil concentrations and postinfusion pharmacokinetics in infants receiving 0.2% ropivacaine with sufentanil as a continuous epidural infusion for postoperative pain relief. METHODS: With consent of local ethics committee and informed parental consent, 20 infants 3-36 months old (m.o.) (median 9.3 m.o., 9.0 [3.5-15] kg, ASA PS I/II) were enrolled. Epidural catheter was placed under general anesthesia in L3-L4, L4-L5, or L2-L3 interspace and threaded not farther than 4 cm into epidural space. After initial bolus of 0.2% ropivacaine, 0.5 ml·kg(-1) and sufentanil 200 ng·kg(-1) , continuous infusion of 0.2% ropivacaine, 0.3 mg·kg(-1) ·h(-1) with sufentanil 112 ng·kg(-1) ·h(-1) was started. For the postoperative period, sufentanil dose was reduced to 37 ng·kg(-1) ·h(-1) . Blood samples were drawn at the end of surgery, 24 h later, by the end of 2nd day of infusion and after 3, 6, and 18 h from the end of infusion. Sufentanil was measured using liquid-liquid extraction (LLE) procedure and HPLC-MS/MS method with LOQ = 5 pg·ml(-1) . RESULTS AND CONCLUSIONS: Elimination of sufentanil following epidural administration was very slow, with MRT = 28.25 [18.36-44.75] h and t1/2 MRT  = 19.57 [12.72-31.01] h. In infants, during a long-term infusion of sufentanil with ropivacaine, the opioid concentration in plasma increases during the postoperative infusion itself, then increases even further after discontinuation of the infusion, in some cases reaching the values consistent with a potential risk of respiratory depression. Meticulous monitoring of the infants' vital signs is therefore mandatory not only during the infusion, but also for several hours after its discontinuation.

Pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats.

The aim of this study was to compare the pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats. Six adult cats were used. Anesthesia was induced and maintained with isoflurane in oxygen. End-tidal isoflurane concentration was set at 2% and adjusted as required due to spontaneous movement. Fentanyl (10 µg/kg), alfentanil (100 µg/kg), or sufentanil (1 µg/kg) was administered intravenously as a bolus, on separate days. Blood samples were collected immediately before and for 8 h following drug administration. Plasma drug concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to concentration-time data. A 3-compartment model best fitted the concentration-time data for all drugs, except for 1 cat in the sufentanil group (excluded from analysis). The volume of the central compartment and the volume of distribution at steady-state (L/kg) [mean ± SEM (range)], the clearance (mL/min/kg) [harmonic mean ± pseudo-SD (range)], and the terminal half-life (min) [median (range)] were 0.25 ± 0.04 (0.09-0.34), 2.18 ± 0.16 (1.79-2.83), 18.6 ± 5.0 (15-29.8), and 151 (115-211) for fentanyl; 0.10 ± 0.01 (0.07-0.14), 0.89 ± 0.16 (0.68-1.83), 11.6 ± 2.6 (9.2-15.8), and 144 (118-501) for alfentanil; and 0.06 ± 0.01 (0.04-0.10), 0.77 ± 0.07 (0.63-0.99), 17.6 ± 4.3 (13.9-24.3), and 54 (46-76) for sufentanil. Differences in clearance and volume of distribution result in similar terminal half-lives for fentanyl and alfentanil, longer than for sufentanil.

Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both. METHODS: After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. RESULTS: The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. CONCLUSIONS: Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

Determination of total and unbound sufentanil in human plasma by ultrafiltration and LC-MS/MS: application to clinical pharmacokinetic study.

A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of sufentanil total and unbound drug concentrations. Unbound drug was separated by an ultrafiltration step before sample preparation. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated sufentanil used as an internal standard. Separation was performed by gradient elution using UPLC-like system and analysed by MS/MS consisting of an electrospray ionization source. Calibration curves showed linearity in the concentration range of 5-2500 pg/ml for analysis of both total and unbound concentrations of sufentanil. The lower limit of quantification was 5 pg/ml for both total and unbound sufentanil plasma drug concentrations. Intra- and interassay precision and accuracy did not exceed 15%. Method was applied to pharmacokinetic study in patients undergoing coronary artery bypass grafting.

Development and validation of an HPLC/MS/MS method for the determination of sufentanil and morphine in human plasma.

A sensitive and fast HPLC/MS/MS method for measurement of sufentanil and morphine in plasma was developed and validated. A single liquid-liquid extraction in alkaline medium was used for the cleanup of plasma, and fentanyl was added as an internal standard (IS). The analyses were carried out using a C18 column and the mobile phase acetonitrile-5 mM ammonium acetate + 0.25% formic acid (70 + 30, v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source in positive mode was set up in the selective reaction monitoring mode to detect precursor --> product ion transition 387.0 > 238.0, 285.7 > 165.1, and 337.0 > 188.0 for sufentanil, morphine, and IS, respectively. The method was linear in the 0.05 (LOQ) - 500 ng/mL range for sufentanil and 10 (LOQ) - 1000 ng/mL range for morphine. Good selectivity, linearity, precision, accuracy, and robustness were obtained for the HPLC/MS/MS method. The proposed method was successfully applied for the determination of sufentanil and morphine in patients undergoing cardiac surgery.

Comparison of dispersive liquid-liquid microextraction and hollow fiber liquid-liquid-liquid microextraction for the determination of fentanyl, alfentanil, and sufentanil in water and biological fluids by high-performance liquid chromatography.

Dispersive liquid-liquid microextraction (DLLME) and hollow fiber liquid-liquid-liquid microextraction (HF-LLLME) combined with HPLC-DAD have been applied for the determination of three narcotic drugs (alfentanil, fentanyl, and sufentanil) in biological samples (human plasma and urine). Different DLLME parameters influencing the extraction efficiency such as type and volume of the extraction solvent and the disperser solvent, concentration of NaOH, and salt addition were investigated. In the HF-LLLME, the effects of important parameters including organic solvent type, concentration of NaOH as donor solution, concentration of H(2)SO(4) as acceptor phase, salt addition, stirring rate, temperature, and extraction time were investigated and optimized. The results showed that both extraction methods exhibited good linearity, precision, enrichment factor, and detection limit. Under optimal condition, the limits of detection ranged from 0.4 to 1.9 µg/L and from 1.1 to 2.3 µg/L for DLLME and HF-LLLME, respectively. For DLLME, the intra- and inter-day precisions were 1.7-6.4% and 14.2-15.9%, respectively; and for HF-LLLME were 0.7-5.2% and 3.3-10.1%, respectively. The enrichment factors were from 275 to 325 and 190 to 237 for DLLME and HF-LLLME, respectively. The applicability of the proposed methods was investigated by analyzing biological samples. For analysis of human plasma and urine samples, HF-LLLME showed higher precision, more effective sample clean-up, higher extraction efficiency, lower organic solvent consumption than DLLME.

Impact of CYP3A4*1G polymorphism on metabolism of fentanyl in Chinese patients undergoing lower abdominal surgery.

PURPOSE: This study aimed to investigate the impact of CYP3A4*1G genetic polymorphism on metabolism of fentanyl in Chinese patients undergoing lower abdominal surgery. METHODS: 176 patients receiving elective lower abdominal surgery under general anesthesia were recruited into this study. Genotyping of CYP3A4*1G was carried out by direct sequencing. The plasma fentanyl concentration was detected 30 min after anesthesia induction by high performance liquid chromatography-ultraviolet ray (HPLC-UV). The visual analog scale (VAS) was used for pain evaluation at rest during patient-controlled analgesia (PCA) treatment 0 h, 12 h and 24 h after operation. PCA fentanyl consumption and adverse effects were recorded during the first 24 h after surgery. RESULTS: The frequency of CYP3A4*1G variant allele was 0.227 (80/352, 95% CI 0.165, 0.289) in these patients. After grouping according to the genotype of CYP3A4*1G, plasma fentanyl concentration in the *1/*1 variant (wild-type) group (12.8±6.5 ng/ml) was significantly lower than that in the *1/*1G group (16.8±9.0 ng/ml, P<0.01) and the *1G/*1G group (28.1±9.5 ng/ml, P<0.01). Patients in the *1G/*1G group (247.1±73.2 µg) consumed significantly less fentanyl than that in either the wild-type group (395.0±138.5 µg) or the *1/*1G group (359.8±120.2 µg) (P<0.01). There was a significant correlation between plasma fentanyl concentration and PCA fentanyl consumption (r=-0.552, P<0.001). CONCLUSIONS: CYP3A4*1G polymorphism is related to the pharmacokinetics of fentanyl, and patients with CYP3A4*1G variant A allele have a lower metabolic rate of fentanyl. The specific CYP3A4*1G polymorphism may predict the individual requirement of fentanyl.

Rapid UPLC-MS/MS method for the determination of sufentanil in human plasma and its application in target-controlled infusion system.

A rapid, selective and highly sensitive ultra-performance liquid-chromatography mass-spectrometry (UPLC-MS/MS) method has been developed and validated for the determination of sufentanil in human plasma. Sufentanil was separated on an ACQUITY™ UPLC BEH C(18) column (50 mm × 2.1 mm, ID 1.7 µm) and analyzed in positive-ion (PI) electrospray-ionization (ESI) mode. The mobile phase (MP) consisted of acetonitrile:water (45:55, v/v) under isocratic conditions at a flow rate of 0.2 ml/min. Sufentanil and internal-standard (IS) fentanyl were eluted at 1.47 and 1.16 min, respectively, and their responses were optimized at the transitions m/z 387.2>238.0 and m/z 337.2>188.0, respectively. The calibration curve was linear over the range 0.071-4.56 ng/ml, with coefficients of determination >0.999. The accuracy and precision of the method were between 96.49% and 100.37% (RSD<9%), and the mean recovery of sufentanil was 84.08 ± 7.29%. The method was successfully applied to evaluate the predictive accuracy of Gepts pharmacokinetic sets in a target-controlled infusion (TCI) model, and the Gepts parameters were capable of predicting sufentanil plasma concentrations when multi-level target concentrations were acquired during surgery.

Pharmacokinetics of sufentanil administered by target-controlled infusion in Chinese surgical patients.

BACKGROUND: Target-controlled infusion (TCI) has been recently developed and successfully implemented in clinical practice. This study was conducted to determine the pharmacokinetics of TCI administered sufentanil in Chinese surgical patients. METHODS: The pharmacokinetics of sufentanil was investigated in 12 adult patients, aged 23-76 years, scheduled for prolonged surgery under general anesthesia. Anesthetic induction was carried out with propofol, rocuronium and TCI administered sufentanil aiming for target effect-site concentration of sufentanil 4 or 6 ng/ml. Sufentanil TCI lasted for 30 minutes. Frequent arterial blood samples (1.5 ml) were drawn during and up to 24 hours after sufentanil TCI. Plasma sufentanil concentrations were measured by liquid chromatography-tandem mass spectrometry; limit of sensitivity of mass spectrometry was 5 pg/ml. The data were analyzed with the nonlinear mixed-effect model program. RESULTS: The pharmacokinetics of TCI administered sufentanil were optimally described by a three-compartment model with the following parameters: the central volume of distribution (V(1))=5.4 L, the volume of distribution at steady-state (Vdss)=195.4 L, systemic clearance (Cl(1))=1.10 L/min, and elimination half-life (t(1/2) gamma)=271.8 minutes. Both age and gender affected the pharmacokinetic parameters. The rapid distribution clearance (Cl(2)) was negatively correlated with patient age, and the volume of slowly equilibrating compartment (V(3)) was positively correlated with age. The Cl(2) and the volume of rapidly equilibrating compartment (V(2)) were influenced by gender with male patients showing higher values of Cl(2) and V(2) than female patients. There was no relationship of body weight, lean body mass, plasma albumin, or target effect-site concentration of sufentanil with any of the pharmacokinetic parameters studied. CONCLUSIONS: The pharmacokinetics of TCI administered sufentanil in Chinese patients can be adequately described by a three-compartment model. Pharmacokinetics adjusted to the individual patient should improve the accuracy of TCI systems.

[Effect of target-controlled infusion sufentanil in different doses combined with nitrogen monoxide inhalation on hemodynamics and postoperative recovery].

OBJECTIVE: To investigate the effect of target-controlled infusion sufentanil in different doses combined with inhalation anesthesia at 0.9 minimum alveolar concentration (MAC) on the intraoperative hemodynamics and postoperative recovery of spontaneous breathing. METHODS: Sixty patients aged 18-65, weighing 45-80 kg, undergoing colectomy or pedical screw intermix were randomized into 3 groups: Groups S3, S4, and S5 to receive sufentanil at the fixed target plasma concentrations of 0.3, 0.4, and 0.5 ng/ml respectively in combination of nitrogen monoxide inhalation at 0.9 MAC. The arterial blood pressure (ABP), heart rate (HR), electrocardiogram (ECG), and pulse blood oxygen saturation during anesthesia were monitored, the time between the termination of anesthetic use and recovery of spontaneous breathing and extubation were observed, and the use of vasoactive drug and other intravenous anesthetics were recorded. RESULTS: The BP and HR were nearly stable during the anesthesia in three groups. The values of time from termination of anesthesia to recovery of spontaneous breathing of Groups S2, S3, and S5 were (3.3 +/- 2.0) min, (2.8-2.5) min, and (6.1-3.4) min) respectively without significant differences among them. The time from termination of anesthetic use to extubation of Group S5 was 14.6 +/- 10.9 min, significantly longer than those of Groups S3 and S4: [(9.6 +/- 8.0) and (9.4 +/- 6.4) min, both P < 0.05]. CONCLUSION: When the concentration of inhalation anesthetic is at 0.9 MAC, the target plasma sufentanil concentration of 0.3 ng/ml is adequate in anesthesia. If sufentanil infusion was terminated 50 min before the end of surgery, the patients can recover safely and quickly.

High sensitive determination of sufentanil in human plasma of parturients and neonates following patient-controlled epidural analgesia (PCEA).

A validated method for the determination of sufentanil in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is described. Sufentanil was extracted from human plasma with solid-phase-extraction using deuterated sufentanil, [(2)H(5)]-sufentanil, as internal standard. Sufentanil and the internal standard were determined with an API 4000 tandem mass spectrometer equipped with a Turbo-V-Source operating in positive ESI mode on an Alltima HP HILIC straight phase column. The method showed a lower limit of quantification of 0.25 pg/ml (12.5 fg on column). The applicability of the method is shown in a clinical study, in which levels of sufentanil in plasma of parturients and arterial umbilical plasma of their neonates following patient-controlled epidural analgesia (PCEA) under several regimen treatments was analyzed.