Pharmacokinetics Of Fentanyl Research Articles

A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer-related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter- and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side-effects and increasing its efficacy.

Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

PurposeTransdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route.MethodsFifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model.ResultsA one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h−1, respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed.ConclusionsWe describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-2005-x) contains supplementary material, which is available to authorized users.

Population Pharmacokinetics of Fentanyl in the Critically Ill.

To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Prospective cohort study. Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients with acute respiratory failure and/or shock who received fentanyl during the first 5 days of their ICU stay. We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to 5 days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 μg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found that fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance, intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 L/hr (95% CI, 32-39 L/hr), 55 L/hr (95% CI, 42-68 L/hr), 203 L (95% CI, 140-266 L), and 523 L (95% CI, 428-618 L), respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart diseases were included. In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients.

Effects of acepromazine or dexmedetomidine on fentanyl disposition in dogs during recovery from isoflurane anesthesia

ObjectiveTo describe fentanyl pharmacokinetics during isoflurane anesthesia and on recovery from anesthesia with concurrent administration of acepromazine, dexmedetomidine or saline in dogs. Study designExperimental blinded, randomized, crossover study. AnimalsSeven adult hound dogs. MethodsDogs were administered intravenous (IV) fentanyl as a bolus (5 μg kg−1) followed by an infusion (5 μg kg−1 hour−1) for 120 minutes during isoflurane anesthesia and emergence from anesthesia, and for 60 minutes after extubation during recovery from anesthesia. At the time of extubation, dexmedetomidine (2.5 μg kg−1), acepromazine (0.05 mg kg−1) or saline were administered IV. Venous blood was sampled during the maintenance and recovery periods. Fentanyl plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry and population pharmacokinetic analyses were performed. ResultsMean fentanyl plasma concentrations were 1.6-4.5 ng mL−1 during isoflurane anesthesia and 1.6-2.0 ng mL−1 during recovery from anesthesia. Recovery from isoflurane anesthesia without sedation was associated with an increase in the volume of the central compartment from 0.80 to 1.02 L kg−1. After administration of acepromazine, systemic clearance of fentanyl increased from 31.5 to 40.3 mL minute−1 kg−1 and the volume of the central compartment increased from 0.70 to 0.94 L kg−1. Administration of dexmedetomidine did not significantly change fentanyl pharmacokinetics. Inter-individual variability for fentanyl parameter estimates in all treatments ranged from 2.2% to 54.5%, and residual error ranged from 6.3% to 13.4%. Conclusions and clinical relevanceThe dose rates of fentanyl used in this study achieved previously established analgesic plasma concentrations for the duration of the infusion. Despite alterations in fentanyl pharmacokinetics, differences in fentanyl plasma concentrations among treatments during recovery from anesthesia were small and were unlikely to be of clinical significance.

The Influence of Low Salivary Flow Rates on the Absorption of a Sublingual Fentanyl Citrate Formulation for Breakthrough Cancer Pain

ContextSalivary gland hypofunction may affect the absorption of drugs through the oral mucosa, which in turn may affect their clinical efficacy (e.g., onset of action). ObjectivesThe aim of this study was to assess the pharmacokinetics of a sublingual fentanyl orally disintegrating tablet (Abstral®, Prostrakan Inc.) in a group of cancer patients with salivary gland hypofunction. MethodsNine cancer patients with salivary gland hypofunction underwent a series of three pharmacokinetic studies with the sublingual fentanyl orally disintegrating tablet. In the first phase, the patients received no pretreatment; in the second phase, the patients were allowed to moisten the oral cavity before dosing; in the third phase, the patients were given pilocarpine hydrochloride (saliva stimulant) before dosing. Fentanyl concentrations were measured using a method of high-performance liquid chromatography with validated tandem mass spectrometric detection. ResultsThe Tmax was longer, the Cmax was lower, the AUC0-30 lower, and the AUClast lower in the phase involving no pretreatment; the Tmax/Cmax/AUC0-30/AUClast were similar in the phase involving moistening of the oral cavity and the phase involving giving pilocarpine hydrochloride. ConclusionThe pharmacokinetics of the sublingual fentanyl orally disintegrating tablet appear to be negatively affected by the presence of salivary gland hypofunction, although the moistening of the oral cavity before dosing results in a pharmacokinetic profile similar to that seen with the giving of pilocarpine hydrochloride.

Fentanyl with ropivacaine infusion for postoperative pain relief in infants and children. Kinetics of epidural fentanyl.

The aim of the study was to evaluate pharmacokinetics of fentanyl administered as continuous epidural infusion with 0.2% ropivacaine for postoperative pain relief in infants and toddlers, and older children undergoing major abdominal and urological procedures. Thirteen infants and toddlers (median age 14 [range 3-36]months, 11 [5-17]kg, Group I) and 11 children (68 [45-131]months, 21 [16-52] kg, Group II) participated in the study. Epidural catheter was placed under general anesthesia in the L1-L2, L2-L3, or L3-L4 epidural space and threaded up to 4cm into the epidural space. Bolus dose of 0.2% ropivacaine, 0.5ml·kg(-1) and fentanyl, 2μg·kg(-1) was given, then followed by continuous infusion of 0.2% ropivacaine, 0.15ml·kg(-1) ·h(-1) with fentanyl 1.12μg·kg(-1) ·h(-1) . In the postoperative period, fentanyl dose was reduced to 0.375μg·kg(-1) ·h(-1) . With this dosing regimen, fentanyl concentration in plasma was within the range of analgesic concentrations, and did not exceed 1.0ng·ml(-1) . After discontinuation of epidural infusion, pharmacokinetics of fentanyl was complicated by a slight increase in plasma concentration during the elimination phase. Both elimination half-life of fentanyl (t1/2, MRT ) and mean residence time (MRT) were much longer than those observed after single IV bolus dose, and longer in Group I than in Group II (t1/2 MRT 15.9 [3.6-31.5]h vs 8.0 [7.1-13.3]h, P<0.05, MRTstop-last 22.9 [5.1-45.5]h vs 11.5 [10.2-19.1]h, P<0.05). Therefore, monitoring of vital signs seems warranted for several hours after the termination of the epidural infusion because risk of respiratory depression may persist, especially in the younger age group.

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe.

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non-pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5-2ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118-127 gestational days were used. In the first protocol, 1week before surgery, 10 animals received 2μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2μg/kg/hr were applied to antebrachium, and ewes were then given a 2μg/kg intravenous bolus followed by an intra-operative 2.5μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra- and post-operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.

Liquid Chromatography-Tandem Mass Spectrometry Method for the Quantification of Fentanyl and its Major Metabolite Norfentanyl in Critically Ill Neonates

Fentanyl is a widely used opioid analgesic in the intensive care unit. In critically ill neonates, continuously infused fentanyl is part of the standard treatment regimen for sedation and pain control. Little is known about fentanyl pharmacokinetics in specific clinical indications, as in asphyxiated neonates with therapeutic hypothermia treatment. In this report, we introduce a liquid chromatography-tandem mass spectrometry method (LC-MS/MS-method) to determine concentrations of fentanyl and its major metabolite norfentanyl in critically ill newborns. 100 μl serum samples were precipitated with acetonitrile containing the isotopically labeled internal standard fentanyl-D5. The supernatant was evaporated to dryness and reconstituted with mobile phase. Chromatographic separation was achieved on a C18 column with a gradient flow. LC-MS/MS detection was performed using a triple-stage quadrupole mass spectrometer working in selected reaction monitoring mode with positive electrospray ionization. Linearity was demonstrated over the concentration range of 0.1 to 40 and 39.4 ng/ml for fentanyl and norfentanyl respectively. Inter- and intraday accuracies and precisions were within the acceptance ranges. The lower limit of quantification was 0.02 and 0.09 ng/ml for fentanyl and norfentanyl. The method was successfully applied to newborns with hypoxic-ischemic encephalopathy treated with whole body hypothermia, which allowed accurate determination of fentanyl and norfentanyl concentrations as a basis for pharmacokinetic analysis.

Clinical and pharmacokinetic considerations of novel formulations of fentanyl for breakthrough cancer pain.

This review will provide an overview of pharmacokinetics and clinical practice considerations of the novel formulations of fentanyl for the treatment of breakthrough cancer pain. First, we provide a brief description of the physicochemical properties of fentanyl. Second, we describe the basic pharmacokinetics of fentanyl, the specifics of various formulations and how they affect pharmacokinetics of fentanyl. Finally, we offer the perspectives on clinical practices in the proper uses of these products. Advancements in the formulations and delivery of fentanyl have provided a safer and more effective treatment for breakthrough cancer pain. These dosage forms offer overlapping yet distinct pharmacokinetic advantages to allow more choices for physicians and patients in the management of breakthrough cancer pain.

Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study

This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl. CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 μg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl : fentanyl). Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/μg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability. Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl.

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs

The purpose of this study was to compare the pharmacokinetics of two highly protein-bound, lipophilic opioid drugs. Fentanyl (10μg/kg) and buprenorphine (20μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42L/kg) compared to buprenorphine (3.54L/kg). The plasma clearance of fentanyl (38.6mL·min/kg) was faster than buprenorphine (10.3mL·min/kg). The terminal half-life of fentanyl (2.22h) was shorter than buprenorphine (3.96h). Despite similar physicochemical properties including octanol-water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs.

Cardiorespiratory physiological data as an indicator of fentanyl pharmacokinetics and pharmacodynamics in critically ill newborn infants: A case report

Cardiorespiratory physiological data as an indicator of fentanyl pharmacokinetics and pharmacodynamics in critically ill newborn infants: A case report

Fentanyl Pharmacokinetics is not Dependent on Hepatic Uptake by Organic Anion‐Transporting Polypeptide 1B1 in Human Beings

A recent study investigating the pharmacokinetics of fentanyl in Sprague-Dawley rats suggested fentanyl to be a substrate of rat organic anion-transporting polypeptide Oatp. In human beings, the most important OATP for the pharmacokinetics of many drugs is OATP1B1. Therefore, genetic variants of OATP1B1 (SLCO1B1) might modulate fentanyl pharmacokinetics and efficacy in human beings. Sixteen healthy male and female volunteers, homozygous for SLCO1B1*1a (genetic wild-type) (n = 11) or *15 (deficient haplotype carrying the single-nucleotide polymorphisms rs2306283 and rs4149056 and exhibiting altered transport activity; n = 5), were included in this randomized crossover study. The participants received fentanyl (5 μg/kg) intravenously alone or with the OATP inhibitor rifampicin (600 mg single oral dose). The pharmacokinetics of fentanyl and norfentanyl were determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). In addition, fentanyl uptake in vitro was evaluated in OATP1B1 overexpressing HEK293 cells and compared to a mock-transfected cell line. In the clinical trial, fentanyl clearance was 18.8 ± 8.2 mL/min. kg in SLCO1B1*1a and 19.5 ± 1.8 mL/min/kg in SLCO1B1*15 carriers and not significantly different between the genotypes. During rifampicin, fentanyl clearance was 15.0 ± 4.4 mL/min/kg in SLCO1B1*1a and 16.7 ± 5.9 mL/min/kg in SLCO1B1*15 carriers (p > 0.5). In addition, in vitro data also indicate that fentanyl is not transported by OATP1B1. In conclusion, our data indicate that OATP1B1 has no impact on fentanyl pharmacokinetics in human beings.

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.

Intranasal Fentanyl Spray: A Novel Dosage Form for the Treatment of Breakthrough Cancer Pain

To review the pharmacology, pharmacokinetics, clinical efficacy, adverse events, dosing, and administration of intranasal fentanyl spray in the treatment of breakthrough cancer pain (BTCP) in adults. Relevant published data were identified using PubMed from inception to April 2012 using the search terms fentanyl nasal spray, intranasal fentanyl, intranasal fentanyl cancer pain, and fentanyl pectin cancer pain. Only articles evaluating the use of intranasal fentanyl spray for cancer pain were selected. All articles evaluating the pharmacokinetics of intranasal fentanyl or the clinical efficacy of intranasal fentanyl spray for the treatment of BTCP were considered; references of selected articles were manually reviewed to identify further articles. The manufacturer of intranasal fentanyl spray was also contacted to obtain information. Intranasal fentanyl spray gained Food and Drug Administration approval for the treatment of BTCP in adults with cancer receiving stable background opioid therapy for chronic pain. In doses ranging from 100 to 800 μg/spray, intranasal fentanyl spray was found to be more effective than placebo and more effective than oral morphine or oral fentanyl formulations in reducing pain for up to 15-45 minutes; onset of analgesia was also improved with intranasal fentanyl spray. The most commonly observed adverse events included nausea, vomiting, vertigo, and dizziness. For the treatment of BTCP, intranasal fentanyl spray offers improved onset of analgesia compared to other oral therapies; this improved onset of analgesia may closely mimic the typical time course of a BTCP episode. Nasal administration may overcome problems such as nausea, vomiting, or xerostomia that may complicate oral administration of analgesics. Potential disadvantages include uncertainty in treating more than 4 BTCP episodes per 24 hours and a higher cost compared to generically available oral opioid analgesics.

Population Pharmacokinetics of Transdermal Fentanyl in Patients With Cancer-Related Pain

ABSTRACTDetermining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CLfenta (L/h) = 3.53 × (15 − Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.

Mild hypothermia decreases fentanyl and midazolam steady-state clearance in a rat model of cardiac arrest.

Therapeutic hypothermia is widely employed for neuroprotection after cardiac arrest. However, concern regarding elevated drug concentrations during hypothermia and increased adverse drug reaction risk complicates concurrent pharmacotherapy. Many commonly used medications in critically ill patients rely on the cytochrome P450 3A isoform for their elimination. Therefore, our study objectives were to determine the effect of mild hypothermia on the in vivo pharmacokinetics of fentanyl and midazolam, two clinically relevant cytochrome P450 3A substrates, after cardiac arrest and to investigate the mechanisms of these alterations. Prospective, randomized, controlled study. University research laboratory. Thirty-two adult male Sprague-Dawley rats. An asphyxial cardiac arrest rat model was used and mild hypothermia (33°C) was induced 1 hr post injury by surface cooling and continued for 10 hrs to mimic the prolonged clinical application of hypothermia accompanied by intensive care interventions. Fentanyl and midazolam were independently administered by intravenous infusion and plasma and brain concentrations were analyzed using ultraperformance liquid chromatography tandem mass spectrometry. Cytochrome P450 3a2 protein expression was measured and a Michaelis-Menten enzyme kinetic analysis was performed at 37°C and 33°C using control rat microsomes. Mild hypothermia decreased the systemic clearance of both fentanyl (61.5 ± 11.5 to 48.9 ± 8.95 mL/min/kg; p < .05) and midazolam (89.2 ± 12.5 to 73.6 ± 12.1 mL/min/kg; p < .05) after cardiac arrest. The elevated systemic concentrations did not lead to parallel increased brain exposures of either drug. Mechanistically, no differences in cytochrome P450 3a2 expression was observed, but the in vitro metabolism of both drugs was decreased at 33°C vs. 37°C through reductions in enzyme metabolic capacity rather than substrate affinity. Mild hypothermia reduces the systemic clearances of fentanyl and midazolam in rats after cardiac arrest through alterations in cytochrome P450 3a2 metabolic capacity rather than enzyme affinity as observed with other cytochrome P450s. Contrasting effects on blood and brain levels further complicates drug dosing. Consideration of the impact of hypothermia on medications whose clearance is dependent on P450 3A metabolism is warranted.

Impact of CYP3A5 and ABCB1 Gene Polymorphisms on Fentanyl Pharmacokinetics and Clinical Responses in Cancer Patients Undergoing Conversion to a Transdermal System

The aim of this study was to evaluate the influence of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system. Sixty Japanese cancer patients being treated with a fentanyl transdermal reservoir system according to the current Japanese guidelines were enrolled. Blood samples were obtained 192 h after conversion to the fentanyl transdermal system. Clinical responses after fentanyl application were evaluated by determining the incidences of adverse effects and rescue medication. The plasma concentration of fentanyl normalized with the measured absorption rate was significantly higher in the CYP3A5*3/*3 group than in the *1/*1 and *1/*3 groups (p = 0.048 and 0.021, respectively). Greater incidences of central adverse effects were observed in CYP3A5*3/*3 patients than in *1/*1+*1/*3 patients (odds ratio [OR], 3.49; 95% confidence interval [95% CI], 1.13-10.75; p = 0.029). Fewer patients with the ABCB1 1236TT allele than the 1236C allele needed rescue medication (OR, 0.17; 95% CI, 0.03-0.89; p = 0.036). CYP3A5*3 affected the pharmacokinetics of fentanyl and increased the incidence of central adverse effects. ABCB1 1236TT was associated with decreased administration of rescue medication after switching to the transdermal fentanyl system. In conclusion, these gene polymorphisms may predict clinical responses to fentanyl in cancer patients being converted to the transdermal system.

Pharmacokinetics of Fentanyl in Male and Female Rats after Intravenous Administration

The sex difference of fentanyl (CAS 990-73-8) pharmacokinetics was investigated after intravenous administration to male and female rats at a dose of 0.03 mg/kg. The plasma concentrations of fentanyl disappeared mono-phasically in both male and female rats. Plasma concentrations and pharmacokinetic parameters were not significantly different in male and female rats, but plasma concentrations of fentanyl in female rats were lower than those in male rats until 1 h after administration. The distribution volume in female rats was 1.34 times larger than that in male rats. In a previous study, the C(max) and AUC(0-infinity) values in female rats were significantly lower than those in male rats after subcutaneous administration of fentanyl. Since no sex difference in the pharmacokinetic parameters of fentanyl were observed after intravenous administration in the present study, the sex difference of the pharmacokinetics of fentanyl after subcutaneous administration may be explained by delayed distribution from the dosing site to the systemic circulation in female rats relative to male rats, which may be attributable to a higher content of subcutaneous fat in female rats.

A low blood volume LC‐MS/MS assay for the quantification of fentanyl and its major metabolites norfentanyl and despropionyl fentanyl in children

Preterm and term neonates often require surgical procedures and analgesia. However, our knowledge about neonatal pharmacokinetics of fentanyl, the most commonly used drug for these procedures, and its metabolites is still incomplete. To facilitate pharmacokinetic studies of fentanyl and its metabolites in neonates and other children, we developed and validated an LC-MS/MS method based on minimally invasive, low blood volume sampling. LC-MS/MS was used for the simultaneous analysis of fentanyl, despropionyl fentanyl (DPF), and norfentanyl from dried blood samples (DBS) collected on filter paper. Positive ions were monitored using multiple reaction monitoring. Since the standard matrix for measuring fentanyl blood concentrations is plasma, the assay was developed and validated in plasma, whole blood, and then DBS. Our method was able to measure clinically relevant levels of fentanyl and its metabolites. In DBS, the lower limits of quantification were 100 pg/mL for fentanyl with a range of reliable response from 0.1 to 100 ng/mL (r(2)>0.99) and 250 pg/mL for both DPF and norfentanyl with a range of reliable response from 0.25 to 100 ng/mL (r(2)>0.99). In plasma and in DBS inter-day accuracy and precisions of fentanyl met predefined acceptance criteria and also indicated comparable assay performance in both matrices.