Pharmacokinetic considerations of regional administration and drug targeting: Influence of site of input in target tissue and flux of binding protein
Tóm tắt
Huntet al. introduced the concept of the Drug Targeting Index (DTI) to quantify the gain associated with regional drug administration and targeting and showed that for the ideal case of all drug first reaching the targetDTI=1+CL
s/(Q
T(1−E
T)) whereCL
s is the total clearance of drug from the body (including the target tissue),Q
T is the target blood flow andE
T is the steady-state extraction ratio of the drug in the target. In the model they portrayed the tissue as a homogeneous organ. A more general pharmacokinetic model has been developed that takes into account the three anatomical spaces (vascular, interstitial, and intracellular) of the target organ or tissue and that, in addition to unbound drug permeating the vascular and cellular membranes, protein-bound drug can also flux between the vascular and interstitial spaces. Elimination of unbound drug can take place from the cellular and interstitial spaces. An important parameter influencing theDTI is shown to be the fraction of targeted dose that is eliminated there before it reaches the systemic circulation,f
T. Equations have been developed showing the relationship betweenf
T andE
T and forDTI when drug is administered at the various sites within the tissue and under a variety of conditions. Only when drug is administered into the target arterial blood stream or when distribution of drug within the target tissue is perfusion rate-limited, doesf
T=E
T andDTI=1+CL
s/(Q
T·(1−E
T)). Otherwise consideration needs to be given to the permeabilities of both the unbound and bound drug and site of target administration, interstitial or intracellular. Thenf
T is greater thanE
T andDTI is greater than that expected had perfusion-rate limited distribution prevailed. The maximum benefit inDTI is seen for a drug of low cellular permeability but high cellular intrinsic clearance administered intracellularly.
Tài liệu tham khảo
C. A. Hunt, R. D. MacGregor, and R. A. Siegel. Engineering targetedin vivo drug delivery. I. The physiological and physiochemical principles governing opportunities and limitations.Pharm. Res. 3:333–344 (1986).
S. Øie and J-D. Huang. Influence of administration route on drug delivery to a target organ.J. Pharm. Sci. 70:1344–1347 (1981).
R. L. Dedrick. Interspecies scaling of regional delivery.J. Pharm. Sci. 75:1047–1052 (1986).
U. G. Eriksson and T. N. Tozer. Pharmacokinetic evaluation of regional drug delivery.Acta Pharm. Jugoslavia 37:331–344 (1987).
R. A. Siegel, R. D. MacGregor, and C. A. Hunt. Comparison and critique of two models of regional drug delivery.J. Pharmacokin. Biopharm. 19:365–372 (1991).
H. Suzuki, D. Nakai, T. Seita, and Y. Sugiyama. Design of a drug delivery system for targeting based on pharmacokinetic considerations.Adv. Drug Delivery Rev. 19:335–357, 1996.
V. J. Stella and A. S. Kearney. Pharmacokinetics of drug targeting: specific implications for targeting via prodrugs in drug targeting and delivery. InHandbook of Pharmacology, Vol. 100, Academic Press, San Diego, 1991, pp. 71–103.
M. Weiss. On pharmacokinetics in target tissues.Biopharm. Drug Dispos. 6:57–66 (1985).
A. Aubree-Lecat, M-C. Duban, S. Demignot, M. Domurado, P. Fiurnie, and D. Domurado. Influence of barrier-crossing limitations on the amount of macromolecular drug taken up by its target.J. Pharmacokin. Biopharm. 21:75–98 (1993).
T. Sakane, M. Nakatsu, A. Yamamoto, M. Hashida, H. Sezaki, S. Yamashita, and T. Nadai. Assessment of drug disposition in the perfused rat brain by statistical moment analysis.Pharm. Res. 8:683–689 (1991).
K. Ohkouchi, H. Imoto, Y. Takakura, M. Hashida, and H. Sezaki. Disposition of anti-cancer drugs after bolus administration into a tissue-isolated tumour perfusion system.Cancer Res. 50:1640–1644 (1990).
R. Atsumi, K. Endo, T. Kakutani, Y. Takakura, M. Hashida, and H. Sezaki. Disposition characteristics of mitomycin C-dextran conjugate in normal and tumour-bearing muscles of rabbits.Cancer Res. 47:5546–5551 (1987).
K. Mihara, M. Mori, T. Hojo, Y. Takakura, H. Sezaki, and M. Hashida. Disposition characteristics of model macromolecules in the perfused rat kidney.Biol. Pharm. Bull. 16:158–162 (1993).
E. Nara, M. Masegi, T. Hatono, and M. Hashida. Pharmacokinetic analysis of drug absorption from muscle based on a physiological diffusion model: effect of molecular size on absorption.Pharm. Res. 9:161–168 (1992).
E. P. Sipos and H. Brem. New delivery systems for brain tumour therapy.Neurol. Clin. 13:813–825 (1995).
M. F. Flessner and R. L. Dedrick. Monoclonal antibody delivery to intraperitoneal tumours in rats: effects of route of administration and intraperitoneal solution osmolality.Cancer Res. 54:4376–4384 (1994).
S. G. Owen, H. W. Francis, and M. S. Robert. Disappearance kinetics of solutes from synovial fluid after intra-articular injection.Br. J. Clin. Pharmacol. 38:349–355 (1994).
V. J. Stella and K. J. Himmelstein. Prodrugs and site-specific drugs delivery.J. Med. Chem. 23:1277–1282 (1980).
F. A. Omar, H. Farag, and N. Bodor. Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbonate-type ester.J. Drug Target. 2:309–316 (1994).
N. Bodor. Designing safer ophthalmic drugs by soft drug approaches.J. Ocular Pharmacol. 10:3–15 (1994).
M. E. Brewster, K. Raghavan, E. Pop, and N. Bodor. Enhanced delivery of ganciclovir to the brain through the use of redox targeting.Antimicrob. Agents Chemother. 38:817–823 (1994).
S. W. Martin, A. J. Stevens, B. S. Brennan, M. L. Reis, L. A. Gifford, M. Rowland, and J. B. Houston. Regional drug delivery: Permeability characteristics of the rat 6-day-old air pouch model of inflammation.Pharm. Res. 12:1980–1986 (1995).
L. W. Seymour. Passive tumour targeting of soluble macromolecules and drug conjugates.Crit. Rev. Ther. Drug. Carrier Syst. 9:135–187 (1992).
C. Sung, R. J. Youle, and R. L. Dedrick: Pharmacokinetic analysis of immunotoxin uptake in solid tumours: role of plasma kinetics, capillary permeability and binding.Cancer Res. 50:7382–7292 (1990).
Y. F. Huang, R. N. Upton, W. B. Runciman, and L. E. Mather. Insight into interstitial drug disposition: Lymph concentrations of lidocaine, procainamide and meperidine in the hindquaters of unanaesthetized and anaesthetized sheep.J. Pharmacol. Exp. Ther. 256:69–75 (1991).
M. Nishikawa, A. Kamijo, T. Fujita, Y. Takakura, H. Sezaki, and M. Hashida. Synthesis and pharmacokinetics of new liver-specific carrier, glycosylated carboxymethyldextran and its application to drug targeting.Pharm. Res. 10:1253–1261 (1993).
E. J. F. Franseen, F. Moolenaar, D. Dezeeuw, and D. K. F. Meijer. Drug targeting to the kidney with low molecular weight proteins.Adv. Drug Delivery Rev. 14:67–88 (1994).
L. J. Nugent and R. K. Jain. Two-compartment model for plasma pharmacokinetics of individual vessels.J. Pharmacokin. Biopharm. 12:451–462 (1984).
C-H. Chou, A. J. McLachlan, and M. Rowland. Membrane permeability and lipophilicity in the isolated perfused rat liver: 5-ethyl barbituric acid and other compounds.J. Pharmacol. Exp. Ther. 275:933–940 (1995).
A. V. Boddy, L. J. Aarons, and K. Petrak. Steady state considerations using a three-compartment model.Pharm. Res. 6:367–372 (1989).