96
to 200 min could be fitted to log AU/ At = (-k'/2.303) t-mid +
intercept, and the apparent rate constant (k1) 0.0394 min ^ (half-life
= 18 min) corresponded with the plasma second distributional half-life
of 26 min (Table 2, Fig. 24a). In dog B at 1.6369 mg/kg dose (Study #2),
the excretion rate plot for M (Fig. 24b) gave an apparent rate constant
0.0046 min 1 (half-life = 150 min). In the same dog at this dose level,
the excretion rate plot of buprenorphine could be fitted into two
separate linear segments (Fig. 25), from which the two apparent rate
constants obtained were, 0.019 min ^ (half-life = 37 min), and 0.0011
min 1 (half-life = 622 min). Both these half-lives corresponded with
the half-lives obtained from the plasma data (Table 2, 39 and 654 min).
Clearances of Buprenorphine (1) and Conjugate (M)
Renal clearance of buprenorphine. Upon rearrangement of equation
19,
dU/dt = ku Vc Cp Eq. 28
Integrating between 0 to U (time; 0 to t),
t
£U = kV f Cp dt = Cl AUC. Eq. 29
u c qJ r ren t ^
where AUC^ is the area under the plasma concentration-time curve. The
renal clearance of buprenorphine (Cl^en ) estimated from the slopes
1 1
of cumulative amounts excreted in urine EU against AUCfc averaged
1.91 _+ 0.96 (SEM) ml/min (Table 2), which indicate high protein binding
if unbound drug excreted solely by glomerular filtration.
These clearance plots (Figs. 26-28) frequently did not go through
the origin and could be best characterized by one or more straight lines
conforming to the equation,