Towards an untargeted mass spectrometric approach for improved screening in equine antidoping.

The emergence of novel doping agents is a continuous issue for analysts who aim to maintain the integrity of horseracing together with the well-being and safety of the animals and riders involved. Untargeted mass spectrometric analysis presents a potential improvement for antidoping as it enables the detection of compounds being indirectly affected by an administered drug. In this study, liquid chromatography-high-resolution mass spectrometry was used to investigate a 12-horse administration study of the synthetic opioid, butorphanol. A mass spectrometric workflow capable of detecting metabolic differences for an extended period of time was successfully developed. This proof-of-concept study demonstrates the potential of untargeted workflows to provide a list of biomarkers of exposure and effect that are indicative of drug administration which may be implemented into routine testing for improved doping control.

The intravenous pharmacokinetics of butorphanol and detomidine dosed in combination compared with individual dose administrations to exercised horses.

In equine and racing practice, detomidine and butorphanol are commonly used in combination for their sedative properties. The aim of the study was to produce detection times to better inform European veterinary surgeons, so that both drugs can be used appropriately under regulatory rules. Three independent groups of 7, 8 and 6 horses, respectively, were given either a single intravenous administration of butorphanol (100 µg/kg), a single intravenous administration of detomidine (10 µg/kg) or a combination of both at 25 (butorphanol) and 10 (detomidine) µg/kg. Plasma and urine concentrations of butorphanol, detomidine and 3-hydroxydetomidine at predetermined time points were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The intravenous pharmacokinetics of butorphanol dosed individually compared with co-administration with detomidine had approximately a twofold larger clearance (646 ± 137 vs. 380 ± 86 ml hr-1  kg-1 ) but similar terminal half-life (5.21 ± 1.56 vs. 5.43 ± 0.44 hr). Pseudo-steady-state urine to plasma butorphanol concentration ratios were 730 and 560, respectively. The intravenous pharmacokinetics of detomidine dosed as a single administration compared with co-administration with butorphanol had similar clearance (3,278 ± 1,412 vs. 2,519 ± 630 ml hr-1  kg-1 ) but a slightly shorter terminal half-life (0.57 ± 0.06 vs. 0.70 ± 0.11 hr). Pseudo-steady-state urine to plasma detomidine concentration ratios are 4 and 8, respectively. The 3-hydroxy metabolite of detomidine was detected for at least 35 hr in urine from both the single and co-administrations. Detection times of 72 and 48 hr are recommended for the control of butorphanol and detomidine, respectively, in horseracing and equestrian competitions.

Peripheral α2-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs.

OBJECTIVE: We determined the possible effects of a peripherally acting α2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam. STUDY DESIGN: Randomized, experimental, blinded crossover study. ANIMALS: Six healthy Beagle dogs. METHODS: Two IM treatments were administered: 1) medetomidine hydrochloride (20 µg kg-1) + butorphanol (100 µg kg-1) + midazolam (200 µg kg-1; MBM) and 2) MBM + MK-467 hydrochloride (500 µg kg-1; MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0-100 mm). Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (Cmax) and time to Cmax (Tmax) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments. RESULTS: Data from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM-MK. The Tmax values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.

Plasma concentrations and sedative effects of a dexmedetomidine, midazolam, and butorphanol combination after transnasal administration in healthy rabbits.

Plasma concentrations of dexmedetomidine (D = 0.1 mg/kg), midazolam (M = 2 mg/kg), and butorphanol (B = 0.4 mg/kg) were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) after their simultaneous (DMB) transnasal (TN) administration to healthy rabbits. Time-dependent changes in sedation and antinociception were evaluated by measuring a sedation score based on rabbit's posture, loss of the righting, palpebral and pedal withdrawal reflexes and by instrumental monitoring of rectal temperature, heart rate, arterial blood pressure, pulse-oximetry, and capnometry. The peak plasma concentration (Cmax ) of each drug was reached within 5 min (Tmax ) from DMB-TN administration along with deep sedation and analgesia. Such effects subsided after 45 min into a moderate sedation and analgesia lasting for additional 15 min. All rabbits awakened spontaneously and uneventfully 90 min after DMB-TN administration. During the anesthetic procedure, arterial blood pressure markedly decreased and respiratory depression ensued requiring oxygen supplementation. The results of this study show that all three molecules of the DMB combination were absorbed through the TN route, inducing deep sedation and analgesia suitable for minor surgical procedures. Such combination should be used with caution in rabbits bearing cardiovascular or respiratory diseases because of its ability to induce hypotension and respiratory depression.

Pharmacokinetics of butorphanol delivered with an osmotic pump during a seven-day period in common peafowl (Pavo cristatus).

OBJECTIVE: To determine pharmacokinetics of butorphanol delivered via osmotic pumps in common peafowl (Pavo cristatus) as a method for analgesic administration to avian species. ANIMALS: 14 healthy adult male common peafowl. PROCEDURES: A preliminary experiment was conducted with 2 birds to establish time point and concentration requirements. Then, the remaining 12 birds were anesthetized, and 2 osmotic pumps containing butorphanol (volume, 2 mL; mean dosage, 247 µg/kg/h) were implanted subcutaneously in each bird for 7 days prior to removal. Blood samples were collected before pump implantation (time 0); 3, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours after pump implantation; and 3 and 6 hours after pump removal. Plasma butorphanol concentrations were measured via liquid chromatography-mass spectrometry. RESULTS: Plasma concentrations peaked (mean, 106.4 µg/L; range, 61.8 to 133.0 µg/L) at a mean of 39.0 hours, with no evidence of sedation in any bird. After pump removal, butorphanol was rapidly eliminated (half-life, 1.45 hours; range, 1.31 to 1.64 hours; n = 5). Mean clearance per fraction of dose absorbed was 2.89 L/kg/h (range, 2.00 to 5.55 L/kg/h). Mean amount of time the plasma butorphanol concentration was ≥ 60 µg/L was 85.6 hours (range, 3.5 to 155.3 hours). CONCLUSIONS AND CLINICAL RELEVANCE: Plasma concentrations of butorphanol in common peafowl were maintained at or above reported efficacious analgesic concentrations. This study established a method for administering analgesics to avian patients without the need for frequent handling or injections. Use of these osmotic pumps may provide options for avian analgesia.

Pharmacokinetics and pharmacodynamics comparison between subcutaneous and intravenous butorphanol administration in horses.

The study objective was to compare butorphanol pharmacokinetics and physiologic effects following intravenous and subcutaneous administration in horses. Ten adult horses received 0.1 mg/kg butorphanol by either intravenous or subcutaneous injections, in a randomized crossover design. Plasma concentrations of butorphanol were measured at predetermined time points using highly sensitive liquid chromatography-tandem mass spectrometry assay (LC-MS/MS). Demeanor and physiologic variables were recorded. Data were analyzed with multivariate mixed-effect model on ranks (P ≤ 0.05). For subcutaneous injection, absorption half-life and peak plasma concentration of butorphanol were 0.10 ± 0.07 h and 88 ± 37.4 ng/mL (mean ± SD), respectively. Bioavailability was 87%. After intravenous injection, mean ± SD butorphanol steady-state volume of distribution and clearance was 1.2 ± 0.96 L/kg and 0.65 ± 0.20 L/kg/h, respectively. Terminal half-lives for butorphanol were 2.31 ± 1.74 h and 5.29 ± 1.72 h after intravenous and subcutaneous administrations. Subcutaneous butorphanol reached and maintained target plasma concentrations >10 ng/mL for 2 ± 0.87 h (Mean ± SD), with less marked physiologic and behavioral effects compared to intravenous injection. Subcutaneous butorphanol administration is an acceptable alternative to the intravenous route in adult horses.

Development and evaluation of oral osmotic pump of butorphanol tartrate.

Butorphanol is potent analgesic useful in pain management. However, because of high first-pass metabolism butorphanol is not available in market as oral dosage form. Drugs that undergo extensive first-pass metabolism can be delivered orally if protected in the stomach, and proximal small intestine. An oral controlled porosity osmotic pump (CPOP) was designed to deliver butorphanol tartrate that can maintain therapeutic blood concentration up to 24 h. The target release profile for extended release formulation was calculated by Wagner Nelson de-convolution using published immediate release blood concentration data for oral route. Composition of the core and coating were optimized using USFDA approved ingredients by evaluation of the drug release. Drug release from the developed system was inversely proportional to the weight gain and directly related to the level of pore former. Scanning electron microscopy (SEM) confirmed the formation of pores in the coating membrane on contact with water which lead to drug to release. Kinetic models were applied to drug release data to establish the drug release mechanism. The developed osmotic system effectively delivers selected drug at a predetermined rate for extended period.

Pharmacokinetics and pharmacodynamics of butorphanol following intravenous administration to the horse.

Butorphanol is a narcotic analgesic commonly used in horses. Currently, any detectable concentration of butorphanol in biological samples collected from performance horses is considered a violation. The primary goal of the study reported here was to update the pharmacokinetics of butorphanol following intravenous administration, utilizing a highly sensitive liquid chromatography-mass spectrometry (LC-MS) assay that is currently employed in many drug-testing laboratories. An additional objective was to characterize behavioral and cardiac effects following administration of butorphanol. Ten exercised adult horses received a single intravenous dose of 0.1 mg/kg butorphanol. Blood and urine samples were collected at time 0 and at various times for up to 120 h and analyzed using LC-MS. Mean±SD systemic clearance, steady-state volume of distribution, and terminal elimination half-life were 11.5±2.5 mL/min/kg, 1.4±0.3 L/kg, and 5.9±1.5 h, respectively. Butorphanol plasma concentrations were below the limit of detection (LOD) (0.01 ng/mL) by 48 h post administration. Urine butorphanol concentrations were below the LOD (0.05 ng/mL) of the assay in seven of 10 horses by 120 h post drug administration. Following administration, horses appeared excited as noted by an increase in heart rate and locomotion. Gastrointestinal sounds were markedly decreased for up to 24 h.

Qualitative and quantitative characteristics of the electroencephalogram in normal horses after sedation.

BACKGROUND: The administration of certain sedatives has been shown to promote sleep in humans. Related agents induce sleep-like behavior when administered to horses. Interpretation of electroencephalograms (EEGs) obtained from sedated horses should take into account background activity, presence of sleep-related EEG events, and the animal's behavior. HYPOTHESIS: Sedatives induce states of vigilance that are indistinguishable on EEGs from those that occur naturally. ANIMALS: Six healthy horses. METHODS: Digital EEG with video was recorded after administration of 1 of 4 sedatives (acepromazine, butorphanol, xylazine, or detomidine). Serum drug concentrations were measured. Recordings were reviewed, states were identified, and representative EEG samples were analysed. These data were compared with data previously obtained during a study of natural sleep. RESULTS: Butorphanol was associated with brief episodes resembling slow wave sleep in 1 horse. Acepromazine led to SWS in 3 horses, including 1 that also exhibited rapid eye movement sleep. Periods of SWS were observed in all horses afer xylazine or detomidine administration. Normal sleep-related EEG events and heart block, occurred in association with SWS regardless of which sedative was used. Spectral data varied primarily by state, but some differences were observed between sedative and natural data. CONCLUSIONS AND CLINICAL IMPORTANCE: Qualitatively, EEG findings appeared identical whether sedation-induced or naturally occurring. The startle response and heart block associated with some sedatives may be related to sleep. Alpha(2) agonists can be used to obtain high quality EEGs in horses, but acepromazine does not promote a relaxed state in all animals.

Pharmacokinetics and physiologic effects of intramuscularly administered xylazine hydrochloride-ketamine hydrochloride-butorphanol tartrate alone or in combination with orally administered sodium salicylate on biomarkers of pain in Holstein calves following castration and dehorning.

OBJECTIVE: To determine the pharmacokinetic parameters of xylazine, ketamine, and butorphanol (XKB) administered IM and sodium salicylate (SAL) administered PO to calves and to compare drug effects on biomarkers of pain and distress following sham and actual castration and dehorning. ANIMALS: 40 Holstein bull calves from 3 farms. PROCEDURES: Calves weighing 108 to 235 kg (n = 10 calves/group) received one of the following treatments prior to sham (period 1) and actual (period 2) castration and dehorning: saline (0.9% NaCl) solution IM (placebo); SAL administered PO through drinking water at concentrations from 2.5 to 5 mg/mL from 24 hours prior to period 1 to 48 hours after period 2; butorphanol (0.025 mg/kg), xylazine (0.05 mg/kg), and ketamine (0.1 mg/kg) coadministered IM immediately prior to both periods; and a combination of SAL and XKB (SAL+XKB). Plasma drug concentrations, average daily gain (ADG), chute exit velocity, serum cortisol concentrations, and electrodermal activity were evaluated. RESULTS: ADG (days 0 to 13) was significantly greater in the SAL and SAL+XKB groups than in the other 2 groups. Calves receiving XKB had reduced chute exit velocity in both periods. Serum cortisol concentrations increased in all groups from period 1 to period 2. However, XKB attenuated the cortisol response for the first hour after castration and dehorning and oral SAL administration reduced the response from 1 to 6 hours. Administration of XKB decreased electrodermal activity scores in both periods. CONCLUSIONS AND CLINICAL RELEVANCE: SAL administered PO through drinking water decreased cortisol concentrations and reduced the decrease in ADG associated with castration and dehorning in calves.

Pharmacokinetics and intramuscular bioavailability of a single dose of butorphanol in Asian elephants (Elephas maximus).

Captive Asian elephants (Elephas maximus) are susceptible to lameness resulting from foot and joint pain, including chronic arthritis. In the past, opioid analgesics, such as butorphanol, have been used clinically for pain management. However, dosages used in treating elephants were often extrapolated from data in horses, with no pharmacokinetic information on the specific agents used in elephant species. In this pharmacokinetic study, six adult captive Asian elephants (5 female, 1 male castrate) were administered a 0.015 mg/kg dose of butorphanol by both i.v. and i.m. routes. A complete crossover design was used with a 3-wk washout period between treatments. Serial blood samples were collected immediately prior to butorphanol administration and at 5, 10, 20, and 40 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 24 h after administration. The butorphanol analysis was performed using a validated liquid chromatography-mass spectrophotometric assay with a limit of quantitation of 0.025 ng/ml. The mean Cmax after i.m. administration was 7.9 ng/ml, with a corresponding Tmax, of 40 min and t(1/3), of 7.1 h. After i.v. administration, the mean Vd(ss) was 1.4 L/kg and the mean Cl(p) was 0.26 L/kg/h. Mean i.m. bioavailability was 37%. The results indicate that butorphanol used at 0.015 mg/kg i.m. or i.v. could be useful in elephants when given for pain control.

Pharmacokinetics of butorphanol in cats after intramuscular and buccal transmucosal administration.

OBJECTIVE: To determine the pharmacokinetics of butorphanol in cats following IM and buccal transmucosal (BTM) administration, to determine the relative bioavailability of butorphanol following BTM administration, and to extrapolate a plasma concentration associated with antinociception on the basis of existing data from pharmacologic studies of butorphanol in cats. ANIMALS: 6 healthy adult cats. PROCEDURES: Following IM or BTM butorphanol tartrate (0.4 mg/kg) administration to cats in a 2-way crossover trial, plasma samples were obtained from blood collected via a central venous catheter during a 9-hour period. Plasma butorphanol concentrations were determined by high-performance liquid chromatography. RESULTS: Data from 1 cat contained outliers and were excluded from pharmacokinetic analysis. Mean+/-SD terminal half-life of butorphanol for the remaining 5 cats was 6.3+/-2.8 hours and 5.2+/-1.7 hours for IM and BTM administration, respectively. Peak plasma butorphanol concentrations were 132.0 and 34.4 ng/mL for IM and BTM administration, respectively. Time to maximal plasma concentration was 0.35 and 1.1 hours for IM and BTM administration, respectively. Extent of butorphanol absorption was 37.16% following BTM application. On the basis of data from extant pharmacologic studies of butorphanol in cats, mean+/-SD duration of antinociception was 155+/-130 minutes. The estimated plasma concentration corresponding to this time point was 45 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: In cats, IM butorphanol administration at 0.4 mg/kg maintained a plasma concentration of >45 ng/mL for 2.7+/-2.2 hours, whereas BTM administration at the same dose was not effective at maintaining plasma concentrations at >45 ng/mL.

Pharmacokinetics of butorphanol tartrate in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).

OBJECTIVE: To determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in red-tailed hawks (RTHs) and great horned owls (GHOs). ANIMALS: 6 adult RTHs and 6 adult GHOs. PROCEDURES: Each bird received an injection of butorphanol (0.5 mg/kg) into either the right jugular vein (IVj) or the pectoral muscles in a crossover study (1-week interval between treatments). The GHOs also later received butorphanol (0.5 mg/kg) via injection into a medial metatarsal vein (IVm). During each 24-hour postinjection period, blood samples were collected from each bird; plasma butorphanol concentrations were determined via liquid chromatography-mass spectrometry. RESULTS: 2- and 1-compartment models best fit the IV and IM pharmacokinetic data, respectively, in both species. Terminal half-lives of butorphanol were 0.94 +/- 0.30 hours (IVj) and 0.94 +/- 0.26 hours (IM) for RTHs and 1.79 +/- 1.36 hours (IVj), 1.84 +/- 1.56 hours (IM), and 1.19 +/- 0.34 hours (IVm) for GHOs. In GHOs, area under the curve (0 to infinity) for butorphanol after IVj or IM administration exceeded values in RTHs; GHO values after IM and IVm administration were less than those after IVj administration. Plasma butorphanol clearance was significantly more rapid in the RTHs. Bioavailability of butorphanol administered IM was 97.6 +/- 33.2% (RTHs) and 88.8 +/- 4.8% (GHOs). CONCLUSIONS AND CLINICAL RELEVANCE: In RTHs and GHOs, butorphanol was rapidly absorbed and distributed via all routes of administration; the drug's rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs.

[Chemical-toxicological analysis of butorphanol].

The conditions of butorphanol isolation from biological fluids were studied. The method of its extraction with the mix of organic solvents by pH 12 was proposed. How to identify butorphanol with the methods of thin-layer chromatography, ultraviolet spectrometry, high-performance liquid chromatography, gas chromatography with a detector of electron capture, chromato-mass spectrometry was developed. Possibility of use ultraviolet spectrometry for quantitative assessment of butorphanol was shown.

High throughput screening of sub-ppb levels of basic drugs in equine plasma by liquid chromatography-tandem mass spectrometry.

This paper describes a high throughput LC-MS-MS method for the screening of 75 basic drugs in equine plasma at sub-ppb levels. The test scope covers diversified classes of drugs including some alpha- and beta-blockers, alpha- and beta-agonists, antihypotensives, antihypertensives, analgesics, antiarrhythmics, antidepressants, antidiabetics, antipsychotics, antiulcers, anxiolytics, bronchodilators, CNS stimulants, decongestants, sedatives, tranquilizers and vasodilators. A plasma sample was first deproteinated by addition of trichloroacetic acid. Basic drugs were then extracted by solid-phase extraction (SPE) using a Bond Elut Certify cartridge, and analysed by LC-MS-MS in positive electrospray ionization (+ESI) and multiple reaction monitoring (MRM) mode. Liquid chromatography was performed using a short C(8) column (3.3 cm L x 2.1mm ID with 3 microm particles) to provide fast analysis time. The overall instrument turnaround time was 8 min, inclusive of post-run and equilibration time. No interference from the matrices at the expected retention times of the targeted masses was observed. Over 60% of the drugs studied gave limits of detection (LoD) at or below 25 pg/mL, with some LoDs reaching down to 0.5 pg/mL. The inter-day precision for the relative retention times ranged from 0.01 to 0.54%, and that for the relative peak area ratios (relative to the internal standard) ranged from 4 to 37%. The results indicated that the method has acceptable precision to be used on a day-to-day basis for qualitative identification.

Serum concentrations and analgesic effects of liposome-encapsulated and standard butorphanol tartrate in parrots.

OBJECTIVE: To compare serum concentrations of liposome-encapsulated butorphanol tartrate (LEBT) and standard butorphanol tartrate (STDBT) following SC and IM administration, respectively, and to evaluate analgesic effects of LEBT and STDBT after parenteral administration to Hispaniolan parrots. ANIMALS: 11 adult Hispaniolan parrots. PROCEDURE: The ability of LEBT to prolong the duration of analgesia in an avian species was tested. Blood samples were collected at serial time points after SC administration of LEBT (10 mg/kg or 15 mg/kg) or IM administration of STDBT (5 mg/kg). Serum concentrations of butorphanol tartrate were determined by use of a commercial immunoassay that measured parent drug and metabolites. Analgesic efficacy was evaluated in parrots exposed to electrical and thermal stimuli. Foot withdrawal thresholds were recorded at baseline and at serial time points after LEBT (15 mg/kg), liposome vehicle, STDBT (2 mg/kg), or physiologic saline (0.9% NaCl) solution administration. RESULTS: LEBT had a prolonged in vivo release for up to 5 days. Negligible serum butorphanol and butorphanol metabolite concentrations were obtained at 24 hours after IM administration of STDBT. Analgesic efficacy of LEBT as measured by foot withdrawal threshold to noxious thermal and electrical stimuli persisted for 3 to 5 days following SC administration of LEBT. CONCLUSIONS AND CLINICAL RELEVANCE: SC administration of LEBT provided analgesia and detectable serum butorphanol concentrations in Hispaniolan parrots for up to 5 days. The use of LEBT may allow for substantial improvement in long-term pain relief without subjecting birds to the stress of handling and multiple daily injections.

High-performance liquid chromatography of nalbuphine, butorphanol and morphine in blood and brain microdialysate samples: application to pharmacokinetic/pharmacodynamic studies in rats.

A rapid and sensitive assay for quantification of nalbuphine, butorphanol and morphine in blood (50 microL) and brain microdialysate ( approximately 40 microL) samples was developed. Blood samples were extracted with ethyl acetate. Analysis was performed with high-performance liquid chromatography (HPLC) coupled to an electrochemical detector. The mobile phase was a mixture of 0.1 M sodium phosphate buffer, methanol and octane-sulfonic acid with ratio and pH depending on compound and matrix. The limits of quantification in blood samples were 25, 50 and 25 ng/mL for nalbuphine, butorphanol and morphine, respectively and 0.5 ng/mL for morphine in microdialysate samples. Based on sample volume, sensitivity and reproducibility, these assays are particularly suitable for pharmacokinetic/pharmacodynamic studies in rodents.

Bioavailability of intranasal butorphanol administered from a single-dose sprayer.

PURPOSE: The bioavailability and tolerability of single doses of intranasal butorphanol tartrate using a single-dose, metered sprayer were studied. METHODS: In this open-label, randomized, three-way crossover study, 24 healthy volunteers received three treatments: (1) 2 mg of i.v. butorphanol (treatment A), (2) 2 mg of intranasal butorphanol (treatment B), and (3) 1 mg of intranasal butorphanol (treatment C). The three treatments received by each subject were separated by six-day washout periods. Venous blood samples (10 mL each) were obtained from an indwelling catheter at 0 (predose), 5, 10, 15,20,30, and 45 minutes and 1,2,3,4,6,8, 12, and 16 hours after butorphanol administration. Pharmacokinetic parameters were determined using standard noncompartmental methods with log-linear least-squares regression analysis to determine the elimination-rate constants. RESULTS: Intranasal butorphanol 1 and 2 mg administered using unit dose sprayers had a mean bioavailability of approximately 80%, which is higher than the percentage reported with the commercially available multidose product (61-69%). The absorption of intranasal butorphanol was rapid, with a median time to reach maximum concentration of 20 minutes (range, 10-60 minutes). Elimination profiles were comparable among all treatments. There were no clinically significant changes in the results of physical examinations, nasal evaluations, or laboratory tests related to butorphanol treatment. Most adverse effects reported were mild to moderate and as expected for this drug. CONCLUSION: Single-dose intranasal butorphanol was rapidly absorbed and had high absolute bioavailability in healthy volunteers.

Pharmacokinetics of butorphanol tartrate administered from single-dose intranasal sprayer.

PURPOSE: The pharmacokinetics and tolerability of single and multiple doses of intranasal butorphanol tartrate using a single-dose metered sprayer were studied. METHODS: In this randomized, open-label, two-way crossover study, 24 healthy subjects received either 1 or 2 mg of intranasal butorphanol as a single dose (treatment A) and 1 or 2 mg of intranasal butorphanol every six hours for seven doses (treatment B). During phase 1, 12 subjects selected at random received a single 1-mg dose and the other 12 a single 2-mg dose. During phase 2, those who received the 1-mg single dose received 1 mg every six hours for seven doses. During phase 3, those who received the 2-mg single dose received 2 mg every six hours for seven doses. Serial blood samples were collected over 12 hours. Pharmacokinetic parameters were determined using noncompartmental methods. RESULTS: Mean (coefficient of variation) values for the area under the concentration-versus-time curve (AUC) from time zero to infinity (AUC0-infinity) were 4.15 (26.4%) and 10.42 (19.6%) ng.hr/ml after single doses of 1 and 2 mg of butorphanol, respectively. At steadly state, mean values for the AUC from time zero to the dosing interval (AUC0-tau) were 4.82 (40.2%) and 10.60 (22.3%) ng.hr/mL, respectively. The accumulation indices were around 2 for both the 1- and 2-mg doses. Median time to maximum concentration values ranged from 15 to 30 minutes for each treatment. Dose-normalized parameters AUC0-infinity. AUC0-tau and maximum concentration (Cmax) were significantly larger after a single 2-mg versus 1-mg dose (p < 0.05). CONCLUSION: Intranasal butorphanol has rapid absorption and predictable accumulation after multiple doses administered with single-dose metered sprayers. Intranasal administration of butorphanol was well tolerated and adverse events were generally mild to moderate in severity and as expected for this drug.