223
administered metabolite was shorter than the hepatically derived
metabolite supports the hypothesis that the rate-determining step for
metabolite elimination on buprenorphine administration is not the
elimination of the metabolite. The slowest process, the rate of return
of the drug from the deepest tissues, must be the rate determining step
in overall disposition of the drug and the hepatically derived
metabolite.
The volumes of distribution of the central compartment V were
obtained by fitting the post-infusion data to equation 50 using the
54
computer program of Yamaoka et.al. (Appendix I, see also Figs.
72,73). The values of Vc estimated by this procedure were 1.72 and 2.75
L in dog F and G (Studies 13, 14) respectively. The V was also
estimated from equation 10, where the values of the parameters P, A and
B were obtained through equations 16-18. The estimated apparent volumes
of distribution of the central compartment by this procedure were 1.6
and 2.75 L respectively in dogs F and G (Studies 13 and 14).
The estimated total clearances (Cltot =Dose/AUCoo, see equations
51-56 for AUC estimations) for the metabolite were 55 and 166 ml/min
respectively in dogs F and G (Studies 13 and 14). The 95% confidence
limits for these clearances are reported in Table 7. The overall
apparent volumes of distribution of the metabolite in the body estimated
in accordance with equation 13 were 31 and 76.5 L respectively in dogs F
and G (Studies 13 and 14).
Urinary and biliary excretion of the metabolite. The sigma minus
plots (equations 20-24) for the metabolite excretion in bile and urine
are given in Fig. 75 and the estimated apparent rate constants are
reported in the figure's legend. Metabolite excretion in bile had an