title: The pharmacokinetics of butorphanol and its metabolites at steady state following nasal administration in humans.
abstract: 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.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08540-4000, USA.
authors.forename: N N
authors.initials: NN
authors.lastname: Vachharajani
authors.forename: W C
authors.initials: WC
authors.lastname: Shyu
authors.forename: D S
authors.initials: DS
authors.lastname: Greene
authors.forename: R H
authors.initials: RH
authors.lastname: Barbhaiya
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002077:Butorphanol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis; D008297:Male; D013058:Mass Spectrometry
chemical_list: D000701:Analgesics, Opioid; C040803:norbutorphanol; D002077:Butorphanol