Previous studies in vitro on the influence of extracellular protein binding of
Teniposide (
VM26) and
Etoposide (VP16-213) on subsequent cellular uptake by experimental murine
tumor cells [
Cancer Res 38:2549 (1978);
Drug Metab Rev 8:119 (1978)] suggested that a timed-sequential combination of
VM26 and VP16-213 may increase the bioavailability of VP16-213. This was studied clinically in six
cancer patients with
ascites (five ovarian, one rectal) whereby
VM26 (20 mg/m2) was given i.p. 2 h prior to VP16-213 (100 mg/m2; i.p.) In some patients, this regimen was administered i.v. The i.v. regimen was found to be more toxic (myelosuppression,
nausea,
vomiting) than i.p. regimen at same doses of drugs. Several patients remained stable to disease during 1-2 courses of
therapy (3 weeks per course), one patient had partial remission, and has been stable in
her disease for more than 4 months. In two patients, plasma and
ascites fluid was analyzed for VP16-213 and
VM26 by a new reverse-phase high performance liquid chromatography method. Both
VM26 and VP16-213 could be eluted isocratically (28% v/v
acetonitrile in water) from a c18 column with retention times of 6.6 and 13.3 min, respectively. Subsequent pharmacokinetic analysis of one patient suggests that protein binding displacement of VP16-213 in plasma and perhaps
ascites fluid increased the pharmacokinetic volume of distribution (28 l) and reduced the elimination half-life (12 h). The data suggests that VP16-213 is distributed more widely in the body and is represented by a single compartment pharmacokinetic model. Analysis of
VM26 in
ascites and plasma suggests that the so-called "deep pharmacokinetic compartment" represents
ascites equivalent space and that the plasma concentration represents
VM26 as free and
protein-bound
drug in kinetic distinguishable compartments. Determinants of
drug action are potentially composed of a multiplicity of physiological, biochemical, and other factors. The potential for manipulating the pharmacodynamic properties of drugs to achieve greater therapeutic potential needs further study.