127
of the drug and cumulative amounts of M excreted in urine against the
concentration of the metabolite m, at the same time. Such plots
according to the equation 35 are given in Fig. 38. Although this method
does not require any explicit knowledge of the dose or the fraction of
the drug transformed into metabolite, it requires that all of the
metabolite be excreted in the urine, and a constant biliary clearance of
the formed metabolite prior to any possible return to the systemic
circulation. Even though an insignificant fraction of the metabolite
appears in plasma, if all of this plasma metabolite is excreted into the
urine, this method could be applied to to the urinary data to obtain the
above parameters. Regressions according to equation 35 gave the
following clearances ( Cl ^ Clg ) _+ standard error in ml/min (Table
2, Fig. 38); 2.72 + 0.5; 2.06 + 0.029; 3.47 + 0.11; 1.27 + 0.009. The
apparent volumes of distribution V of the metabolite + standard error
m
in ml; 2054 _+ 403; 339 +_ 128; 705 _+ 498; 166 _+ 35. The latter two were
much smaller than the presumed plasma volume (1080 ml, for an hematocrit
of 0.4) in dogs.^ This result is not consistent with the assumption
that the hepatically formed metabolite appearing in the systemic
circulation is completely excreted in urine. Thus urinary excretion may
not be the only route of elimination of the systemic metabolite. In
fact, as it will be shown later, a major fraction of the systemically
circulating metabolite is excreted in bile.
Since an insignificant fraction (% recovery 0.2 _+ 0.08) of
unchanged buprenorphine is excreted in urine, it can now be postulated
that for all practical purposes, the estimated total clearance given as
396 ml/min in Table 2 (based on the unwarrented assumption of the
validities of $ and AUC) is essentially equal to the metabolic