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 i ts 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 6h (q6h) on days 2-5, via nasal administration. Serial blood and urin e samples were collected for 24h after the first dose on day 1 and for 72h at steady state on day 6. Plasma and urine samples were analyzed for free and conjugated butorphanol, HO-B, and NOR-B. The plasma sampl es were analyzed using validated gas chromatography-electron capture n egative chemical ionization-mass spectrometric methods and the urine s amples 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 es timated for NOR-B and conjugated metabolites. AUC(0-->infinity) of but orphanol after the first dose and AUC(0-->tau) at steady state were no t statistically different, indicating that the kinetics of butorphanol were not significantly altered after repeated dosing. Steady state le vels of butorphanol were attained within 3 days (d) of q6h dosing and the accumulation index was 1.2 for butorphanol. Due to a relatively lo ng t(1/2) of 15h of HO-B compared to the dosing interval (q6h), the ac cumulation index was 6.0 for this metabolite. The evaluation of the mo lar plasma concentration ratio of HO-B to butorphanol as a function of time revealed that HO-B exhibits elimination-rate-limited kinetics. S imilarly to butorphanol, steady state levels of HO-B were attained wit hin 3 d of q6h dosing. (C) 1997 by John Wiley & Sons, Ltd.