Back to the Top
I have a compound, when dosed in 30% PEG solution at 2
mg/kg IV and 4 mg/kg IP in rats, showed ~250% IP
bioavailability. In addition, the IP Cmax, observed
at 0.5 hrs, is 1.5 times the conc level as first
sample after IV dose (taken at 2 min). From the IV
dose, the compound has high clearance (60 ml/min/kg)
and high volume (4.5 L/kg). The terminal phases of IV
and IP are slightly different, i.e. IP has a 2 hr
terminal half life vs. 1.4 hrs for IV. PO
administration at 4 mg/kg either in solution or
suspension has terminal phases parallel to that of IV
and bioavailability lower than 100%. While I could
conduct additional IP study at 2 mg/kg, can anybody
offer some plausible explanation for this observation?
The ones I can think of are either clearance
saturation or metabolism auto-inhibition, but with
dose levels only two fold apart, is it possible to
cause more than 200% bioavailability? Thanks.
Lilian Li, Ph.D.
[The full dose is being administered IV? A 2 mg/kg IP dose study would
help address the saturable clearance question. Was the IP terminal
half-life measured at the same concentrations as the IV terminal
half-life? How do the slopes compare at the same concentrations? If the
IP Cpmax (at 2 min) is only 1.5 times the IV value the clearance must
be altered considerably to get a 5-fold increase in AUC (before dose
adjustment) - db]
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)