Detailed pharmacokinetic analysis and subsequent evaluation of myelotoxicity were performed in 55 patients who had been randomized to 4 different doses of epirubicin (40, 60, 90 or 135 mg/m2 given i.v. every 3 weeks). A significantly positive correlation was demonstrated between the AUC and the myelotoxicity of epirubicin. A similar correlation was observed when the metabolite epirubicinol was also considered. The decrease in leucocyte count as expressed by the logarithmic ratio between nadir WBC and initial WBC was linearly correlated with the AUC of either epirubicin alone (r=−0.55,P<0.001) or epirubicin and epirubicinol together (r=−0.63,P<0.001). As a relationship between the concentration of epirubicin in a single plasma sample taken at 6 h following i.v. administration and the AUC of the drug has been established, a log-linear relationship between the expected decrease in leucocytes and the concentration at 6 h after administration could be calculated. The proposed model is expressed as the equation: log WBCnadir=log WBCinitial−0.0073×c6 (ng/ml) −0.14.

Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m2. In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (mean t1/2 gamma, 21.6 +/- 7.9 h; range, 10.6-69 h; n = 110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (mean t1/2 gamma, 18.1 +/- 4.8 h; range, 8.2-38.4 h; n = 105). Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (mean t1/2 gamma, 13 +/- 4.6 h; range, 2.7-29 h; n = 104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC = 9.44 x c2 + 62.5 x c24 + 157.7 (r = 0.953).

The pharmacokinetics of doxorubicin in rabbits preloaded either with ammonium chloride or sodium hydrogencarbonate have been investigated following single IV administration of 5 mg/kg.

The permeability of gramicidin‐treated human red blood cell membranes to K+ and CI‐ has been measured at normal ionic strength (1) by tracer exchange at steady‐state distribution of salt, and (2) by net transport of salt in the presence of a salt concentration gradient. Under both conditions KCI was the only inorganic salt in cells and medium. In the studies of self‐exchanges the electrical driving force on the ions was zero. Calculation of permeability coefficients from net salt transport was simplified because the experiment was designed as a special case of the Nernst‐Planck diffusion regime, i.e. the single salt case. Gramicidin altered the cell membranes from being anion to become cation selective. Gramicidin increased the potassium exchange without affecting, the chloride exchange measurably. The chloride exchange showed saturation kinetics as does chloride exchange in normal cells. The net transport of KCI in the presence of a constant concentration gradient increased to a constant value with increasing gramicidin concentration. At high gramicidin concentrations (0°C, pH 7.2) the “chloride permeability coefficient” calculated from tracer exchange (1.9×10‐6 cm/s) was 290 times the chloride permeability coefficient calculated from net salt transport (0.65×10‐8 cm/s). The latter value corresponds to a chloride conductance of 4.2×10‐6 ohm‐1 cm‐2. The chloride permeability coefficient was 2.1×10‐8 cm/s at 25°C (pH 6.8) indicating a value of 3 for the Q25. It appears that normal red cells are anion selective in the sense that anion permeability exceeds cation permeability with a factor of more than a hundred between 0°C and body temperature. The anion exchange, i.e. the Hamburger shift, is a tightly coupled transport process which is several orders of magnitude faster than anion transport by salt diffusion.

THE human red cell membrane is as impermeable to K and Na ions (P=10−11 cm s−1) as an unmodified lipid bilayer1 and has a low permeability (P=10−8 cm s−1) to Cl moving as a free ion. A permeability coefficient of 10−11 cm s−1 is as low as that estimated for unmodified lipid bilayer membranes, which are essentially impermeable to alkali metal cations and anions. Because of this low permeability, studies of active and passive ion transport that require control of both ion concentration and ionic strength have been virtually restricted to work on red cell ghosts prepared by haemolysis and on perfused giant squid axons3. Here we give a principle for altering rapidly and drastically the intracellular ionic strength by varying the concentrations of monovalent cations and anions.

ABSTRACT The transport of the antineoplastic drug doxorubicin,(Adriamy- cin) in human,red blood cells was investigated by measuring,the net efflux from loaded cells. Previous data indicated that doxorubicin,transport was a Fickian diffusion transport process of the electrically neutral molecule through,the lipid domain of the cell membrane (Dalmark, 1981 [In press]). However, doxorubicin transport showed,saturation kinetics and a concentration-dependent,tempera- ture dependence,with nonlinear,Arrhenius plots. The two,phenomena,were related to the doxorubicin,partition coefficient between,1-octanol and a water phase. This relationship indicated,that the two phenomena,were caused,by changes,in the physicochemical,properties of doxorubicin,in the aqueous,phase and were not caused by interaction of doxorubicin,with cell membrane,com- ponents. The physicochemical,properties of doxorubicin,varied with concentra- tion and temperature,because of the ability of doxorubicin,to form polymers,by self-association in aqueous,solution like other planar aromatic molecules through pi-electron orbital interaction. The hypothesis,is proposed,that doxorubicin transport across cell membranes,takes place by simple Fickian diffusion.