Separation of enantiomers of butorphanol and cycloamine by capillary zone electrophoresis.

Butorphanol tartrate is a synthetic opioid agonist-antagonist used as analgesic, possessing three chiral centres in the basic part of the molecule. Its chiral purity is routinely controlled only by optical rotation. A new capillary zone electrophoresis method, capable to separate the enantiomers of butorphanol and intermediate of its synthesis, cycloamine, was developed. Different electrolyte composition (type and concentration of carrier ion, pH, and organic solvent addition), and type and concentration of several chiral selectors (natural and modified cyclodextrins) were tested. Using the optimized conditions (acidic electrolyte with the addition of highly sulphated gamma-cyclodextrin) as low as 0.05% of undesirable enantiomers can be detected. Selected method characteristics, i.e., linearity (0-50 mg/l), precision (2.5% at 20 mg/l), and accuracy (101 +/- 2% at 20 mg/l) were evaluated. The optimized method was applied for the analysis of real batches of butorphanol and cycloamine. It was found that butorphanol tartrate manufactured by IVAX Pharmaceuticals contains less than 0.05% of undesirable enantiomer.

The pharmacokinetics of butorphanol and its metabolites at steady state following nasal administration in humans.

The single-dose and steady state pharmacokinetics of butorphanol and its metabolites, hydroxybutorphanol (HO-B) and norbutorphanol (NOR-B), were studied in nine healthy male volunteers. Each subject received a single 1 mg dose of butorphanol on days 1 and 6, and a 1 mg dose every 6 h (q6h) on days 2-5, via nasal administration. Serial blood and urine samples were collected for 24 h after the first dose on day 1 and for 72 h at steady state on day 6. Plasma and urine samples were analyzed for free and conjugated butorphanol, HO-B, and NOR-B. The plasma samples were analyzed using validated gas chromatography-electron capture negative chemical ionization-mass spectrometric methods and the urine samples were analyzed using a validated HPLC procedure. In the plasma, conjugated metabolites were not detected and only trace amounts of NOR-B were present. Therefore, pharmacokinetic parameters could not be estimated for NOR-B and conjugated metabolites. AUC0-->infinity of butorphanol after the first dose and AUC0-->tau at steady state were not statistically different, indicating that the kinetics of butorphanol were not significantly altered after repeated dosing. Steady state levels of butorphanol were attained within 3 days (d) of q6h dosing and the accumulation index was 1.2 for butorphanol. Due to a relatively long t1/2 of 15 h of HO-B compared to the dosing interval (q6h), the accumulation index was 6.0 for this metabolite. The evaluation of the molar plasma concentration ratio of HO-B to butorphanol as a function of time revealed that HO-B exhibits elimination-rate-limited kinetics. Similarly to butorphanol, steady state levels of HO-B were attained within 3 d of q6h dosing.

High-performance liquid chromatographic method for the quantitative determination of butorphanol, hydroxybutorphanol, and norbutorphanol in human urine using fluorescence detection.

A sensitive, quantitative reversed-phase high-performance liquid chromatographic method has been established for the simultaneous determination of butorphanol, a synthetic opioid, and its metabolites, hydroxybutorphanol and norbutorphanol, in human urine samples. The method involved extraction of butorphanol, hydroxybutorphanol, and norbutorphanol from urine (1.0 ml), buffered with 0.1 ml of 1.0 M ammonium acetate (pH 6.0), onto 1-ml Cyano Bond Elut columns. The eluent was evaporated under nitrogen and low heat, and reconstituted with the HPLC mobile phase, acetonitrile-methanol-water (20:10:70, v/v/v), containing 10 mM ammonium acetate and 10 mM TMAH (pH 5.0). The samples were chromatographed on a reversed-phase octyl 5-microns column. The analysis was accomplished by detection of the fluorescence of the three analytes, at excitation and emission wavelengths of 200 nm and 325 nm, respectively. The retention times for hydroxybutorphanol, norbutorphanol, the internal standard, and butorphanol were 5.5, 9.0, 13.0, and 23.4 min respectively. The validated quantitation range of the method was 1-100 ng/ml for butorphanol and hydroxybutorphanol, and 2-200 ng/ml for norbutorphanol in urine. The observed recoveries for butorphanol, hydroxybutorphanol, and norbutorphanol were 93%, 72%, and 50%, respectively. Standard curve correlation coefficients of 0.995 or greater were obtained during validation experiments and analysis of study samples. The method was applied on study samples from a clinical study of butorphanol, providing a pharmacokinetic profiling of butorphanol.

[Opioid receptor interactions of butorphanol, a narcotic antagonist analgesic, and its metabolites].

The Opioid receptor affinities of butorphanol (BT) and its main metabolites, norbutorphanol (NB) and hydroxybutorphanol (HB), were determined by an in vitro receptor binding assay using crude synaptosomal membrane preparations of rat brain. BT showed high affinities to all types of the receptor except the alpha type (phencyclidine binding site), resulting in displacements of the bindings of mu (dihydromorphine)-, delta (D-Ala2-D-Leu5-enkephalin)- and kappa (ethylketocyclazocine)-ligands with more potency than morphine and ketocyclazocine, and it preferentially bound to mu- and kappa-opioid receptors. NB bound to the mu-binding site with affinity higher than that of pentazocine and to the kappa-binding site with the lowest affinity. HB exclusively bound to the mu-binding site with lower affinity. The affinities of BT, NB, HB and morphine to the alpha-site were smaller than those of pentazocine and ketocyclazocine. In the presence of 100 mM NaCl or by treating with 500 microM 5,5'-dithiobis (2-nitrobenzoic acid), the binding capacity of the membrane preparation was altered, and BT behaved as a typical antagonist. NB showed an agonistic property, and HB behaved as an antagonist. BT appears to be a mu-opioid receptor antagonist and has a kappa-receptor agonist-like character.

[Physical dependence liabilities of butorphanol, a narcotic antagonist, and its main metabolites, norbutorphanol and hydroxybutorphanol].

After the intravenous injection of butorphanol or norbutorphanol in rats every 1 hr for 3 days, naloxone-induced body weight loss and withdrawal syndrome were observed to some degree. A slow-released emulsion containing each of the test drugs was injected subcutaneously in guinea-pigs, and naloxone was administered after 2 or 3 days. BT caused little jumping response even at a dose of 600 mg/kg, and the reaction was significantly weaker than that of pentazocine. No jumping responses were recognized in the cases of NB (600 mg/kg). In morphinized rats, the injection of BT or HB caused potent body weight loss, and these rats exhibited withdrawal syndrome which was more potent than that by pentazocine at the same dose. The body weight losses by the injection of NB and pentazocine were to the same degree, and these changes were significantly different from that of the saline control. BT inhibited the adenylate cyclase activity of the rat caudate nuclei, and the effect was weaker than that of pentazocine. NB showed a slight inhibition, and HB had no effect on the activity. These results suggest that the physical dependence liability of butorphanol is less than that of pentazocine, and the potent mu-antagonistic character of butorphanol is based on the liability. NB, a mu-agonist, makes dependence production possible. The ability of HB is negligible.

The effect of peripherally administered satiety substances on feeding induced by butorphanol tartrate.

Endogenous opioid peptides appear to play a role in the initiation of feeding. Butorphanol, an exogenous opiate which preferentially generalizes to the kappa-sigma opiate receptors, is a potent initiator of feeding. In these studies, we examined the effect of peripherally administered putative satiety substances, cholecystokininoctapeptide, somatostatin, bombesin, gastrin-releasing peptide, thyrotropin-releasing hormone, calcitonin and glucagon on butorphanol induced feeding. With the exception of bombesin, all the other putative satiety factors required 2 to 32 times as high a dose to significantly suppress feeding following butorphanol compared to the dosages required to suppress starvation or tail pinch induced feeding. Bombesin appeared to be approximately equipotent in all systems tested. Haloperidol and atropine both suppressed butorphanol induced feeding supporting our previous hypothesis of an integral relationship between acetylcholinergic-dopaminergic and opioid mechanisms in the initiation of feeding. The findings reported here are compatible with an important role for opioid mechanisms in the initiation of feeding.

Adrenal modulation of opiate induced feeding.

Endogenous opioids have been shown to initiate feeding in sated animals. In the present study adrenalectomy enhanced the feeding response to the kappa opiate agonist, ethylketocyclazocine and the kappa/sigma opiate agonist, butorphanol tartrate. Adrenalectomy abolished the anorectic effect of naloxone at doses as high as 10 mg/kg. Corticosterone replacement did not alter the opiate induced feeding and adrenal demedullated rats continued to show enhancement to opiate induced feeding. These data suggest that in addition to the central nervous system, the adrenal medulla is involved in opiate related induction of feeding.

Butorphanol tartrate: an intravenous analgesic for outpatient surgery.

Many surgical procedures in otolaryngology, particularly those in the areas of facial plastic surgery, are best performed under a local anesthetic. The majority of these procedures may be done on an outpatient basis and require an intravenous analgesic of some form. This analgesic must be safe, predictable, easy to administer, have a rapid onset, and provide good amnesia. A short recovery period is imperative. Diazepam has been widely used in the outpatient setting, since it generally fulfills the requirements listed. However, the recovery time is often prolonged and unpleasant for the patient. Butorphanol tartrate, a synthetic narcotic, provides rapid analgesia in an intravenous dose, fulfills the other requirements for an analgesic agent suitable for outpatient use, and has a relatively short duration. Butorphanol tartrate has been used in an intravenous drip form for outpatient surgical procedures for the past 18 months. Its use in 400 cases representing a broad spectrum of facial plastic procedures has been closely monitored in both the operative and postoperative periods and the results tabulated. We have found butorphanol tartrate to be an excellent agent for local anesthetic procedures in the outpatient setting.

The effects of aging on opioid modulation of feeding in rats.

Feeding responses to naloxone and butorphanol tartrate were measured in Fisher-344 rats with ages of 2, 12, 22 and 28 months. The two younger groups were 10-100 times more sensitive than the older groups to the suppressive effects of naloxone on feeding. Additionally, the older rats were less responsive to the feeding enhancement following butorphanol injections. These results are consistent with reports of age-related changes in endogenous opioid systems.

Cardiopulmonary effects of butorphanol tartrate in dogs.

The effects of butorphanol given (IV) at dose levels of 0.1 and 0.4 mg/kg were evaluated in conscious dogs, n = 5 for each dose. Mild sedation occurred, though it was greater in dogs given the larger dose. Two dogs in each group panted, but PaCO2 was not significantly changed. Small, but significant, decreases in arterial blood pressure, heart rate, and PaO2 occurred (P less than 0.05). Base excess developed a negative trend. The PCV and total protein decreased slightly in dogs given the smaller dose, but were unchanged with the larger dose. Plasma glucose remained within acceptable limits.

Double-blind comparison of butorphanol tartrate and meperidine hydrochloride in balanced anaesthesia.

Butorphanol tartrate, a synthetic morphinan which has analgesic agonist and antagonist properties, was compared with meperidine for balanced anaesthesia. The two agents were found to be comparable in efficacy, maintenance of cardiovascular stability, and incidence of side-effects. Butorphanol has the advantage of being non-narcotic and having a lower propensity for addiction. Because of its antagonist properties, there appears to be a limit to its depressant effects on respiration.