© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 480-487, Copyright © 1997 by Oxford University Press
RL Dedrick and MF Flessner
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.
REVIEWS
Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure
Biomedical Engineering and Instrumentation Program, National Center for Research Resources, National Institutes of Health, Bethesda, MD 20892, USA.
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