231
metabolite during the initial period (upto 4 h) was attributable to the
bile and urine flow dependent biliary and urinary clearances of the
metabolite (see Fig. 79a,b). However, urinary clearance was not pH
dependent (Fig. 79c).
The clearances estimated from the plots of the urinary or biliary
excretion rates against the plasma concentration of the metabolite at
the mid-point of the biological fluid collection interval (Fig. 80)
corresponded with the clearanaces estimated from the sigma minus plots
(See figure legends 77,78 and 80).
Oral Bioavailability of Buprenorphine in Dogs.
Buprenorphine is almost completely hepatically metabolized in dogs.
First pass metabolism is anci tipa ted upon oral administration. The
amount, A, of the orally administered dose Xg, that eventually reaches
the systemic circulation unchanged is:
A = (1-f. )
pm
f X-
a 0
= f.X
Eg. 60
where f. is fraction of the dose eliminated by first-pass metabolism
pm
before reaching the systemic circulation, f is fraction of the dose
administered that is absorbed unchanged and f is the fraction of the
dose that eventually reaches the systemic circulation intact. The
equation 60 is valid if there is no saturable first-pass liver
metabolism and no gut wall metabolism. Since buprenorphine showed
dose-independent pharmacokinetics in the dose range studied, the total
body clearance of the drug administered IV is
Cl
IV
tot
= X7 / AUCIV
0 oo
Eq. 61
For the same drug administered orally, assuming that there is not gut