Abstract
The local disposition characteristics of mitomycin C (MMC) and five lipophilic prodrugs in rabbit hind leg muscle were examined using an in situ single-pass perfusion experiment. Test compounds inputted into a perfusion line as a rectangular function (unit pulse) were perfused with or without albumin and their outflow patterns were analyzed by statistical moment analysis. In interpretation of statistical moment parameters, the well-stirred model was applied to the local perfusion system based on the plate theory of a chromatographic system and some general pharmacokinetic parameters (the disposition parameters) were derived from the moments. A new theory which elucidates the relationships among the moments for plasma protein binding, unbound (free), and total drug fraction was established based on network theory. Using this system, the following conclusions were made for mitomycin C and its five lipophilic derivatives: (i) In the absence of albumin, an increase in lipophilicity led to an increase in organ clearance and distribution volume; (ii) drug bound to albumin did not transfer to the extravascular space; (iii) in the presence of albumin, an increase in lipophilicity results in a decrease in clearance.
Similar content being viewed by others
References
B. K. Martin. Kinetics of elimination of drugs possessing high affinity for the plasma proteins.Nature 207:959–960 (1965).
J. J. Coffey, F. J. Bullock, and P. T. Schoenemann. Numerical solution of nonlinear pharmacokinetic equations: Effects of plasma protein binding on drug distribution and elimination.J. Pharm. Sci. 60:1623–1628 (1971).
J. G. Wagner. Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances.Eur. J. Clin. Pharmacol. 10:425–432 (1976).
P. J. McNamara, G. Levy, and M. Gibaldi. Effect of plasma protein and tissue binding on the time course of drug concentration in plasma.J. Pharmacokin. Biopharm. 7:195–206 (1979).
K. B. Bischoff and R. L. Dedrick. Thiopental pharmacokinetics.J. Pharm. Sci. 57:1346–1351 (1968).
G. R. Wilkinson and D. G. Shand. A physiological approach to hepatic drug clearance.Clin. Pharmacol. Ther. 18: 377–390 (1975).
K. S. Pang and M. Rowland. Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma, and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance.J. Pharmacokin. Biopharm. 5:625–653 (1977).
M. Rowland, L. Z. Benet, and G. G. Graham. Clearance concepts in pharmacokinetics.J. Pharmacokin. Biopharm. 1:123–135 (1973).
K. Yamaoka, T. Nakagawa, and T. Uno. Statistical moments in pharmacokinetics.J. Pharmacokin. Biopharm. 6:547–558 (1978).
D. J. Cutler. Theory of the mean absorption time, an adjunct to conventional bioavailability studies.J. Pharm. Pharmacol. 30:476–478 (1978).
D. J. Cutler. A linear recirculation model for drug disposition.J. Pharmacokin. Biopharm. 7:101–116 (1979).
M. Weiss and W. Förster. 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).
K. Yamaoka, T. Nakagawa, and H. Tanaka. Recirculatory moment analysis of drugs in man: Estimation of extraction ratio and mean cycle time for single systemic and pulmonary circulation.Chem. Pharm. Bull. 33: 784–794 (1985).
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).
D. M. Himmelblau and K. S. Bischoff.Process Analysis and Simulation: Deterministic Systems, Wiley, New York, 1968.
R. L. Schoenfeld. Linear network theory and tracer analysis.Ann. N. Y. Acad. Sci. 108:69–91 (1963).
A. Rescigno and G. Segre.Drug and Tracer Kinetics, Blaisdell, Waltham, MA, 1966.
S. Riegelman and P. S. Collier. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time.J. Pharmacokin Biopharm. 8:509–534 (1980).
H. Sasaki, E. Mukai, M. Hashida, T. Kimura, and H. Sezaki. Development of lipophilic prodrugs of mitomycin C. I. Synthesis and antitumor activity of la-N-substituted derivatives with aromatic pro-moiety.Int. J. Pharm. 15:49–59 (1983).
H. Sasaki, M. Fukumoto, M. Hashida, T. Kimura, andH. Sezaki. Development of lipophilic prodrugs of mitomycin C. III. Physicochemical and biological properties of newly synthesized alkoxycarbonyl derivatives.Chem. Pharm. Bull 31:4083–4090 (1983).
D. G. Garlick and E. M. Renkin. Transport of large molecules from plasma to interstitial fluid and lymph in dogs.Am. J. Physiol. 219:1595–1605 (1970).
A. E. Taylor and D. N. Granger. Equivalent pore modeling: Vesicles and channels.Federation Proc. 42:2440–2445 (1983).
R. L. Juliano (ed).Drug Delivery System, Oxford University Press, New York, 1980.
G. Gregoriadis. Targeting of drugs.Nature 265:407–411 (1977).
V. Stella and T. Higuchi (eds.).Prodrugs as Novel Drug Delivery Systems, American Chemical Society, Washington DC, 1975.
S. H. Yalkowsky. Solubility and melting point considerations in drug design. In E. B. Roche (ed.),Design of Biopharmaceutical Properties Through Prodrugs and Analogs, American Pharmaceutical Association, Washington DC, 1977, p. 392.
H. Sasaki, T. Kakutani, M. Hashida, and H. Sezaki. Absorption characteristics of the lipophilic prodrug of mitomycin C from injected liposomes and an emulstion.J. Pharm. Pharmacol. 37:461–465 (1985).
H. Sasaki, T. Kakutani, M. Hashida, T. Kimura, and H. Sezaki. Blood dispositions of mitomycin C and lipophilic prodrug after intramuscular and intravenous administration in liposomes and o/w emulsion.Chem. Pharm. Bull. 33:2968–2973 (1985).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kakutani, T., Sumimoto, E. & Hashida, M. Effect of plasma protein binding on drug disposition in muscle tissue: Application of statistical moment analysis and network theory toin situ local single-pass perfusion system. Journal of Pharmacokinetics and Biopharmaceutics 16, 129–149 (1988). https://doi.org/10.1007/BF01062256
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01062256