Abstract
The effect of enzyme induction on the hepatobiliary transport of phenol red (PR) in rats was investigated by application of a new analytical system to determine local drug disposition based on statistical moment theory (T. Kakutani et al., J. Pharmacokin. Bio-pharm. 13:609–631, 1985). Employing the moment parameters obtained from the time courses of plasma and biliary concentrations of PR and its metabolite after intravenous injection, the hepatobiliary transport of PR was theoretically assessed by separating it into component subprocesses such as hepatic uptake, hepatobiliary transfer, and intrahepatic metabolism. The results demonstrated that the acceleration of plasma disappearance of PR caused by pretreatment with phenobarbital (PB), known to induce hepatic enzyme systems, could be attributed to elevation of both hepatic and extrahepatic clearances. While PB did cause bile flow elevation (choleresis) and increased metabolism, these effects were shown to make little contribution to accelerated plasma disappearance of PR, since it was shown that the hepatobiliary excretion of PR was rate-limited by the intrahepatic transfer process, which was unaffected by PB treatment. From the results of this study, this experimental/analysis methodology seems to be useful in obtaining detailed information about hepatobiliary transport of the drug from in vivo data.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
T. Kakutani, K. Yamaoka, M. Hashida, and H. Sezaki. A new method for assessment of drug disposition in muscle: Application of statistical moment theory to local perfusion system. J. Pharmacokin. Biopharm. 13:609–631 (1985).
C. D. Klaassen and J. B. Watkins III. Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol. Rev. 36:1–67 (1984).
E. Fischer, Z. Gregus, and F. Varga. Effects of barbiturates on the hepatic cytochrome P-450 dependent enzyme system and biliary excretion of exogenous organic anions in rats. Digestion 20:115–120 (1980).
F. L. S. Tse, T. Chang, and J. M. Jaffe. Effect of butalbital and phenobarbital pretreatment on antipyrine clearance in the rat. Arch. Int. Pharmacodyn. 279:181–194 (1986).
J. B. Watkins and C. D. Klaassen. Induction of UDP-glucuronyltransferase activities in Gunn, heterozygous and Wistar rat livers by pregnenolone-16α-carbonitrile. Drug Metab. Disp. 10:590–594 (1982).
J. B. Watkins and C.D. Klaassen. Effect of inducers and inhibitors of glucuronidation on the biliary excretion and choleretic action of valproic acid. J. Pharmacol. Exp. Ther. 220:305–310 (1982).
B. L. Finley, P. J. Ashley, A. G. Neptune, and G. S. Yost. Substrate-selective induction of rabbit hepatic UDP-glucuronyltransferases by ethanol and other xenobiotics. Biochem. Pharmacol. 35:2875–2881 (1986).
C. D. Klaassen. Importance of hepatic function on the plasma disappearance and biliary excretion of hexachlorophene. Toxicol. Appl. Pharmacol. 49:113–117 (1979).
D. G. McDevitt, A. S. Nies, and G. R. Wilkinson. Influence of phenobarbital on factors responsible for hepatic clearance of indocyanine green in the rat: Relative contribution of induction and altered liver blood flow. Biochem. Pharmacol. 26:1247–1250 (1977).
S. M. Somani, R. A. Bajaj, T. N. Calvey, and T. Norman. Effect of phenobarbitone on the elimination of neostigmine and its metabolites in bile. Biochem. Pharmacol. 29:2256–2257 (1980).
D. L. Eaton and C. D. Klaassen. Effects of microsomal enzyme inducers on carrier-mediated transport systems in isolated rat hepatocytes. J. Pharmacol. Exp. Ther. 208:381–385 (1979).
C. D. Klaassen. Biliary excretion of drugs: Role of ligandin in newborn immaturity and in the action of microsomal enzyme inducers. J. Pharmacol. Exp. Ther. 195:311–319 (1975).
A. W. Wolkof, C. A. Goresky, J. Sellin, Z. Gatmaitan, and I. M. Arias. Role of ligandin in transfer of bilirubin from plasma into liver. Am. J. Physiol. 236:E638–E648 (1979).
S. A. Bai and F. P. Abramson. Interactions of phenobarbital with propranolol in the dog. 1. Plasma protein binding. J. Pharmacol. Exp. Ther. 222:589–594 (1982).
J. V. Moller and M. I. Sheikh. Renal organic anion transport system: Pharmacological, physiological, and biochemical aspects. Pharmacol. Rev. 34:315–358 (1983).
K. Nishida, C. Tonegawa, T. Kakutani, M. Hashida, and H. Sezaki. Statistical moment analysis of hepatobiliary transport of phenol red in the perfused rat liver. Pharm. Res. 6:140–146 (1989).
L. G. Hart and L. S. Schanker. The chemical forms in which phenol red is secreted into bile of rats. Proc. Soc. Exp. Biol. Med. 123:433–435 (1966).
K. Yamaoka, Y. Tanigawara, T. Nakagawa, and T. Uno. A pharmacokinetic analysis program (MULTI) for microcomputer. J. Pharm. Dyn. 4:879–885 (1981).
T. Kakutani, E. Nara, and M. Hashida. Statistical moments and disposition parameters in a local perfusion system under mammillary nonequilibrium condition. J. Pharmacokin. Biopharm. 18:449–458 (1990).
M. Weiss. Hemodynamic influences upon the variances of disposition residence time distribution of drugs. J. Pharmacokin. Biopharm. 11:63–75 (1983).
M. Yasuhara, H. Katayama, J. Fujiwara, K. Okumura, and R. Hori. Influence of acute renal failure on pharmacokinetics of phenolsulfonphthalein in rats: a comparative study in vivo and in the simultaneous perfusion system of liver and kidney. J. Pharm. Dyn. 8:377–384 (1985).
C. Fleck and H. Braunlich. Relation between renal and hepatic excretion of drugs. I. Phenol red in comparison with p-amino-hippurate and indocyanine green. Exp. Pathol. 29:179–192 (1986).
A. Despopoulos. Congruence of renal and hepatic excretory functions: Sulfonic acid dyes. Am. J. Physiol. 220:1755–1758 (1971).
T. Kakutani, E. Sumimoto, and M. Hashida. Effect of plasma protein binding on drug distribution in muscle tissue: Application of statistical moment analysis and network theory to in situ local single-pass perfusion system. J. Pharmacokin. Biopharm. 16:129–149 (1988).
R. W. Brauer and R. L. Pessotti. Hepatic uptake and biliary excretion of bromosulphthalein in the dog. Am. J. Physiol. 162:565–574 (1950).
D. L. Cook, C. A. Lawler, L. D. Calvin, and D. M. Green. Mechanisms of bile formation. Am. J. Physiol. 171:62–74 (1952).
J. H. Kim and S. K. Hong. Urinary and biliary excretions of various phenol red derivatives in the anesthetized dog. Am. J. Physiol. 202:174–178 (1962).
L. G. Hart, A. M. Guarino, and R. H. Adamson. Effects of phenobarbital on biliary excretion of organic acids in male and female rats. Am. J. Physiol. 217:46–52 (1969).
M. Weiss and W. Forster. Pharmacokinetic model based on circulatory transport. Eur. J. Clin. Pharmacol. 16:287–293 (1979).
M. Weiss. Moments of physiological transit time distributions and the time course of drug disposition in the body. J. Math. Biol. 15:305–318 (1982).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kakutani, T., Endo, K., Nara, E. et al. Effect of Chronic Administration of Phenobarbital on the Hepatobiliary Transport of Phenol Red: Assessment by Statistical Moment Analysis. Pharm Res 9, 908–914 (1992). https://doi.org/10.1023/A:1015852916524
Issue Date:
DOI: https://doi.org/10.1023/A:1015852916524