Pharmacokinetic problems in peritoneal drug administration: Tissue penetration and surface exposure

被引:229
作者
Dedrick, RL [1 ]
Flessner, MF [1 ]
机构
[1] UNIV ROCHESTER, MED CTR, DEPT MED, ROCHESTER, NY 14642 USA
来源
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 1997年 / 89卷 / 07期
关键词
D O I
10.1093/jnci/89.7.480
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial, Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model, If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is (D/k)(1/2) and the apparent permeability of the surface of a peritoneal structure is (Dk)(1/2). The permeability-area product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas, Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing, We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs, Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority, Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position.
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页码:480 / 487
页数:8
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共 61 条
[1]  
Adams J D, 1993, J Natl Cancer Inst Monogr, P141
[2]   Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer [J].
Alberts, DS ;
Liu, PY ;
Hannigan, EV ;
OToole, R ;
Williams, SD ;
Young, JA ;
Franklin, EW ;
ClarkePearson, DL ;
Malviya, VK ;
DuBeshter, B ;
Adelson, MD ;
Hoskins, WJ .
NEW ENGLAND JOURNAL OF MEDICINE, 1996, 335 (26) :1950-1955
[3]  
BERK DA, 1995, ANN J BIOMED ENG S1, V23, pS52
[4]   OPTIMIZATION OF DIALYSATE FLOW AND MASS-TRANSFER DURING AUTOMATED PERITONEAL-DIALYSIS [J].
BRANDES, JC ;
PACKARD, WJ ;
WATTERS, SK ;
FRITSCHE, C .
AMERICAN JOURNAL OF KIDNEY DISEASES, 1995, 25 (04) :603-610
[5]  
BUTLER TP, 1975, CANCER RES, V35, P3084
[6]   DIRECT MEASUREMENT OF INTERSTITIAL CONVECTION AND DIFFUSION OF ALBUMIN IN NORMAL AND NEOPLASTIC TISSUES BY FLUORESCENCE PHOTOBLEACHING [J].
CHARY, SR ;
JAIN, RK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (14) :5385-5389
[7]   CONCENTRATION-DEPENDENT DISAPPEARANCE OF FLUOROURACIL FROM PERITONEAL-FLUID IN THE RAT - EXPERIMENTAL-OBSERVATIONS AND DISTRIBUTED MODELING [J].
COLLINS, JM ;
DEDRICK, RL ;
FLESSNER, MF ;
GUARINO, AM .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1982, 71 (07) :735-738
[8]  
COLLINS JM, 1982, PHARM PRINCIPLES CAN, P77
[9]  
CURTI BD, 1993, CANCER RES, V53, P2204
[10]   INTERSPECIES SCALING OF REGIONAL DRUG DELIVERY [J].
DEDRICK, RL .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1986, 75 (11) :1047-1052