197
equation 32 can be written as
B
m
1->M
= Cl- AUC V m
met t m p
Eq. 58
where B is the cumulative amount of metabolite (M) collected in bile,
Cl^et"1 = aPParent metabolic clearance of buprenorphine as M, AUCfc
= area under the plasma concentration-time curve of buprenorphine at
time t, Vm is apparent volume of distribution of the metabolite and m^
is the metabolite concentration in plasma. Thus the apparent metabolic
clearance, C1^^M of buprenorphine as M can be estimated by
multiple linear regression of the cumulative amounts of the hepatically
formed metabolite (M) excreted in bile against the area under the plasma
concentration-time curve of buprenorphine and the corresponding
metabolite concentration in plasma. For dogs E, F and G, these apparent
metabolic clearances obtained from the equation 58 were 182, 261 and 220
ml/min (Fig. 65, Table 5 where areas were calculated using trapezoidal
rule) and the apparent volumes of distribution of the metabolite were
13.6, 281 and 67.6 L respectively. Plots of AB/ At against
the plasma concentrations of either buprenorphine or the metabolite were
usually scattered. Some examples are given in Fig. 66.
Minor metabolites in bile. Three additional peaks that could be
assigned to minor metabolites in the bile were observed in the
chromatograms of the bile samples from dogs E, F and G (studies 9-11).
Typical chromatograms obtained after acid and B -glucuronidase enzyme
hydrolysis of bile are presented in Fig. 67.
Norbuprenorphine rearranges in acid to form
demethoxynorbuprenorphine. When bile was analysed by HPLC following acid
hydrolysis, the peak with the lowest retention time had the same