Exposure to Fentanyl After Transdermal Patch Administration for Cancer Pain Management.

This study aimed to describe exposure after fentanyl transdermal patch administration in patients with advanced cancer to quantify variability around the exposure. Patients (n  =  56) with advanced cancer who received transdermal fentanyl (Durogesic®; median dose, 50 µg/h; range, 12-200 µg/h) provided venous blood samples (n  =  163) at various times (0.5-72 hours) during several patch application intervals. Plasma fentanyl concentration was determined (median, 0.9 µg/L; range, 0.04-9.7 µg/L) by high-performance liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling with NONMEM. A 1-compartment distribution model with first-order absorption and elimination described fentanyl exposure after transdermal patch administration. Fentanyl apparent clearance (between-subject variability [BSV], %) was estimated at 122 L/h/70 kg and 38.5%, respectively. The absorption rate constant was 0.013 h(-1) . Between-occasion variability on apparent clearance was 22.0%, which was lower than BSV, suggesting predictable exposure within the same patient and justifying therapeutic drug monitoring. Except for weight-based dosing, no other patient characteristic could be identified to guide initial fentanyl dose selection in patients with advanced cancer.

Saliva versus Plasma for Pharmacokinetic and Pharmacodynamic Studies of Fentanyl in Patients with Cancer.

PURPOSE: Fentanyl is widely used to relieve cancer pain. However there is great interpatient variation in the dose required to relieve pain and little knowledge about the pharmacokinetic and pharmacodynamic (PK/PD) relationship of fentanyl and pain control. Patients with cancer are fragile and there is reluctance on the part of health professionals to take multiple plasma samples for PK/PD studies. The relationship between plasma and saliva fentanyl concentrations was investigated to determine whether saliva could be a valid substitute for plasma in PK/PD studies. METHODS: One hundred sixty-three paired plasma and saliva samples were collected from 56 patients prescribed transdermal fentanyl (Durogesic, Janssen-Cilag Pty Limited, NSW, Australia) at varying doses (12-200 µg/h). Pain scores were recorded at the time of sampling. Fentanyl and norfentanyl concentrations in plasma and saliva were quantified using HPLC-MS/MS. FINDINGS: Saliva concentrations of fentanyl (mean = 4.84 µg/L) were much higher than paired plasma concentrations of fentanyl (mean = 0.877 µg/L). Both plasma and saliva mean concentrations of fentanyl were well correlated with dose with considerable interpatient variation at each dose. The relationship between fentanyl and norfentanyl concentrations was poor in both plasma and saliva. No correlation was observed between fentanyl concentration in plasma and saliva (r(2) = 0.3743) or free fentanyl in plasma and total saliva concentrations (r(2) = 0.1374). Pain scores and fentanyl concentration in either of the matrices were also not correlated. IMPLICATIONS: No predictive correlation was observed between plasma and saliva fentanyl concentration. However the detection of higher fentanyl concentrations in saliva than plasma, with a good correlation to dose, may allow saliva to be used as an alternative to plasma in PK/PD studies of fentanyl in patients with cancer.

Development, validation and application of an HPLC-MS/MS method for the determination of fentanyl and nor-fentanyl in human plasma and saliva.

Monitoring fentanyl concentration in saliva and plasma may be useful in pharmacokinetic/pharmacodynamic studies. Salivettes(®) have been used widely for collecting saliva samples. However due to its lipophilicity, fentanyl adsorbs to the cotton dental bud (CDB) used in this device. Furthermore, due to dry mouth being a common adverse effect seen in patients treated with opioids, obtaining enough saliva for analysis is often a challenge. Hence, a simple simultaneous method to quantify fentanyl and its metabolite in both human plasma and saliva was developed and validated. A novel extraction method was also developed and validated to recover fentanyl in saliva directly from the CDB. This extraction method utilises acetonitrile to recover the fentanyl directly from the CDB rather than recovery by centrifugation, which is not always possible. Reverse phase chromatographic separation was performed on a Shimadzu LC 20A HPLC system using gradient elution. The electrospray ion source (ESI) was operated in positive ion mode using an Applied Biosystems API 3200 LC/MS/MS as detector. Deuterated fentanyl (D5) and nor-fentanyl (D5) were used as internal standards (IS). The retention times for fentanyl and nor-fentanyl were 3.70 min and 3.20 min respectively. The lower limit of quantitation (LLOQ) was determined to be 0.030 µg/L in plasma and 0.045 in saliva for fentanyl and nor-fentanyl. Acceptable linearity for fentanyl and nor-fentanyl in both plasma and saliva was demonstrated from 0.02 to 10 µg/L (R(2) 0.9988-0.9994). Accuracy for fentanyl and nor-fentanyl in both plasma and saliva samples was between 96% and 108%. Total imprecision expressed as the co-efficient of variation was between 1.0 and 15.5% for both analytes in both matrices. The validated method was applied successfully in 11 paired plasma and saliva samples obtained from patients with cancer pain receiving transdermal fentanyl (Duragesic(®)) at doses from 25 µg to 100 µg.

Effects of rutaecarpine on the metabolism and urinary excretion of caffeine in rats.

Although rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been reported to reduce the systemic exposure of caffeine, the mechanism of this phenomenon is unclear. We investigated the microsomal enzyme activity using hepatic S-9 fraction and the plasma concentration-time profiles and urinary excretion of caffeine and its major metabolites after an oral administration of caffeine in the presence and absence of rutaecarpine in rats. Following oral administration of 80 mg/kg rutaecarpine for three consecutive days, caffeine (20 mg/kg) was given orally. Plasma and urine were collected serially for up to 24 h and the plasma and urine concentrations of caffeine and its metabolites were measured, and compared with those in control rats. The areas under the curve of both caffeine and its three major metabolites (paraxanthine, theophylline, and theobromine) were significantly reduced by rutaecarpine, indicating that caffeine was rapidly converted into the desmethylated metabolites, and that those were also quickly transformed into further metabolites via the hydroxyl metabolites due to the remarkable induction of CYP1A2 and 2E1. The significant induction of ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, and p-nitrophenol hydroxylase strongly supported the decrease in caffeine and its major metabolites in plasma, as well as in urine. These results clearly suggest that rutaecarpine increases the metabolism of caffeine, theophylline, theobromine, and paraxanthine by inducing CYP1A2 and CYP2E1 in rats.

Effects of Oral Rutaecarpine on the Pharmacokinetics of Intravenous Chlorzoxazone in Rats.

It has been reported that hepatic microsomal cytochrome P450 (CYP) 2E1 is responsible for the metabolism of chlorzoxazone (CZX) to 6-hydroxychlorzoxazone. The present study was undertaken to assess the possible interaction of rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, with CZX. Male Spraque-Dawley rats were administered with 80 mg/kg/day of oral rutaecarpine for three consecutive days. Twenty four hr after the pre-treatment with rutaecarpine, the rats were treated with 20 mg/kg of intravenous CZX Rat hepatic microsomes isolated from rutaecarpine-treated rats showed greater (50% increase) activity of p-nitrophenol hydroxylase (a marker of CYP2E1) when compared with the control rats. Compared with control rats, the AUC of CZX was significantly smaller (84% decrease) possibly due to significantly faster CL (646% increase) in rats pretreated with rutaecarpine. This could be, at least partially, due to induction of CYP2E1 by rutaecarpine.

Hepatotoxic and immunotoxic effects produced by 1,3-dibromopropane and its conjugation with glutathione in female BALB/c mice.

To determine a possible role of glutathione (GSH) conjugation in 1,3-dibromopropane (1,3-DBP)-induced hepatotoxicity and immunotoxicity, female BALB/c mice were treated orally with 1,3-DBP. Based on the liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS) analyses, two forms of S-bromopropyl GSH were observed at m/z 427.9 and 429.9 in the positive ESI spectrum with a retention time of 5.29 and 5.23 min, respectively. Following single treatment of mice with 150, 300 or 600 mg/kg 1,3-DBP for 12 hr, the amount of S-bromopropyl GSH was detected maximally in liver homogenates at 600 mg/kg 1,3-DBP. Hepatic GSH levels were significantly decreased by treatment with 1,3-DBP. In a time course study, production of S-bromopropyl GSH rose maximally 6 hr after treatment and decreased gradually thereafter. The liver weights were significantly increased by treatment with 600 mg/kg 1,3-DBP. When mice were treated orally with 600 mg/kg 1,3-DBP for 12 hr, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased by 365- and 83-fold. In addition, oral 1,3-DBP significantly suppressed the antibody response to a T-dependent antigen at 600 mg/kg 1,3-DBP. 1,3-DBP elevated hepatic levels of malondialdehyde and suppressed the activities of some hepatic enzymes involved in anti-oxidation. Taken together, the formation of GSH conjugate with 1,3-DBP may deplete cellular GSH and, subsequently, produce hepatotoxicity and immunotoxicity via damage to the cellular anti-oxidative system.

The effects of rutaecarpine on the pharmacokinetics of acetaminophen in rats.

Rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been shown to be anti-inflammatory as it inhibits cyclooxygenase-2. It induces the activities of hepatic CYP 1A2, 2B, and 2E1 in rats. A possible interaction between rutaecarpine and acetaminophen (APAP) was investigated in male Sprague Dawley rats in the present study. When 25 mg/kg APAP was intravenously administered concurrently with 80 mg/kg rutaecarpine, the area under the curve of APAP in plasma was significantly decreased when compared to that of APAP alone. When the rats were pre-treated orally with 40 and 80 mg/kg rutaecarpine for 3 days, the % value of C(max) and area under the curve of acetaminophen-sulfate conjugate were significantly decreased to 56.4% and 61.7% of the vehicle control group, respectively. These results suggest that rutaecarpine might cause changes in the pharmacokinetic parameters of APAP in rats.