Pharmacokinetics of 4'-deoxy-4'-iodo-doxorubicin in plasma and tissues of tumor-bearing mice compared with doxorubicin.

It has been reported that 4'-deoxy-4'-iodo-doxorubicin (4'-deoxy-4'-I-DX) displays, on experimental tumors, a spectrum of activity comparable to that of doxorubicin, is active when administered orally, is not cardiotoxic, and is cytotoxic to doxorubicin-resistant cells. We have investigated by high-performance liquid chromatography the pharmacokinetics of this drug in comparison with doxorubicin by treating mice bearing colon 38 adenocarcinoma with equal doses of the two drugs i.v. 4'-Deoxy-4'-I-DX, unlike doxorubicin, is transformed into several metabolites. The 13-dihydro derivative is the major metabolite found; in tumor and in all the organs it accounts for 4-7% of the total fluorescent area under the curve, whereas in plasma and liver it accounts for 15 and 34%, respectively. 4'-Deoxy-4'-I-DX disappears from plasma with a terminal half-life of 5 h, which is half the terminal half-life of doxorubicin (11 h), and its efficiency of absorption after oral administration is 27%. Tissue concentrations of 4'-deoxy-4'-I-DX are initially highest in lung and spleen, whereas those of doxorubicin are highest in liver and kidney. 4'-Deoxy-4'-I-DX levels are higher than those of doxorubicin in tumor, spleen, lung, small intestine, brain, pancreas, and ovaries whereas they are similar in heart, liver, kidney, and bone marrow. The rate of elimination of the new analogue is higher than that of doxorubicin from the tumor and all the organs investigated except the liver. The area under the curve of 4'-deoxy-4'-I-DX is similar to that of doxorubicin in tumor and spleen, whereas it is three times lower in heart. This may explain the lack of cardiotoxicity of this new analogue, which is equiactive and equitoxic with doxorubicin on the experimental system tested.

Plasma retinol level reduction by the synthetic retinoid fenretinide: a one year follow-up study of breast cancer patients.

Fenretinide (HPR) is a synthetic retinoid which has been shown to cause a reduction in the incidence of carcinogen-induced epithelial tumors in experimental animals, and it has been chosen to be tested as a chemopreventive agent in humans. A study on plasma concentrations of HPR, of its metabolite N-(4-methoxyphenyl)retinamide (MPR), and on its effects on endogenous retinol was performed in groups of 14 to 18 breast cancer patients who received p.o. daily doses of placebo or 100, 200, and 300 mg of HPR for 6 mo and subsequently 200 mg for an additional 6 mo. After the first 5 mo of treatment, there was a linear relationship between doses of HPR administered and HPR, MPR, and retinol levels. HPR and MPR levels increased with the increase in dose, whereas retinol levels decreased, and the reduction was statistically significant compared with the placebo group after all the doses tested. Plasma retinol binding proteins (RBP) decreased proportionally to retinol (r = 0.96). The effect of HPR on retinol and RBP occurred early, since retinol and RBP levels had already been decreased, compared with the initial levels, by 38% and 26%, respectively, 24 h after a 200-mg HPR dose. After 12 mo of treatment, in patients treated with 200 mg daily, the dose chosen for a chemopreventive trial, HPR and retinol levels were similar to those found at 5 mo, suggesting no drug accumulation and no further retinol reduction, whereas MPR levels were higher. Following interruption of treatment, as HPR decreased, retinol increased with a linear relationship between log levels (r = 0.78); after about 50 days, HPR was present in trace amounts, and retinol levels were in the range of those of the placebo group. These data show that HPR treatment lowers retinol and RBP plasma concentrations. This effect is related to HPR levels and is reversible on cessation of HPR administration.

Effect of verapamil on doxorubicin activity and pharmacokinetics in mice bearing resistant and sensitive solid tumors.

The effect of the combined administration of verapamil (i.p. twice daily) and doxorubicin (i.v. once weekly) was tested in mice bearing the following: (a) a tumor with induced resistance to doxorubicin (B16VDXR melanoma line); (b) a tumor inherently resistant (MXT mammary carcinoma); and (c) four solid tumors sensitive to doxorubicin (B16 melanoma, B16V melanoma line, M5076 reticulum cell sarcoma, and Lewis lung carcinoma). Verapamil, given according to this treatment schedule, reached peak plasma concentrations of 3 microM. Such treatment did not enhance doxorubicin activity on either inherently or induced resistant tumors, whereas it significantly enhanced doxorubicin growth inhibition in all the sensitive tumors except the Lewis lung carcinoma. Doxorubicin pharmacokinetics after administration of the drug alone and in combination with verapamil was analyzed after the first and repeated treatments in animals bearing B16 melanoma or its resistant subline B16VDXR. The resistance of the B16VDXR line was associated with the ability of the tumor to retain less doxorubicin (AUC = 83 micrograms h/g) than the sensitive tumor B16 (AUC = 204 micrograms h/g) in spite of similar initial levels. The potentiating effect of doxorubicin activity by verapamil in B16 melanoma was not associated with increased doxorubicin levels or retention in the tumor, nor were differences in doxorubicin levels or retention found in the B16VDXR line. The combined treatment did not modify doxorubicin pharmacokinetics in plasma, heart, or spleen. These studies suggest that verapamil in vivo is ineffective in potentiating doxorubicin activity in tumors against which doxorubicin is inactive, that sensitive tumors are heterogeneous in their sensitivity to modulation by verapamil, and that this effect is not associated with modification of doxorubicin pharmacokinetics.

Comparative pharmacokinetics and metabolism of doxorubicin and 4-demethoxy-4'-O-methyldoxorubicin in tumor-bearing mice.

It has been reported that 4-demethoxy-4'-O-methyldoxorubicin (4-dm-4'-O-methylDX) is more potent than doxorubicin (DX), equally active in some murine leukemias and solid tumors, and almost devoid of cardiotoxicity. We used HPLC to investigate the metabolism and the disposition of this drug in comparison with DX in mice bearing colon 38 adenocarcinoma SC and treated with IV doses of the two drugs that were equiactive and equitoxic (4-dm-4'-O-methylDX 1 mg/kg; DX 10 mg/kg). 4-Dm-4'-O-methylDX was metabolized to a polar metabolite, presumably 4-demethoxyDX, which was eliminated more slowly than the parent drug from all the organs and accounted for 25%-50% of total fluorescence; traces of two metabolites less polar than the parent drug (2% of total fluorescence) were found only at early times in the liver. In DX-treated mice traces of doxorubicinol (1%-3% of total fluorescence) were found in tumor and organs, and two aglycones were detected only at early times in the liver. In plasma both drugs declined biexponentially and 4-dm-4'-O-methylDX was eliminated slightly faster than DX. The rate of elimination of the new analogue from lung, kidney, spleen, and small intestine was faster than that of DX; in heart and liver 4-dm-4'-O-methylDX was detectable for only up to 24 h, while DX was detectable for up to 7 days. In the tumor the kinetics and the elimination patterns of the two drugs were similar. The distribution of 4-dm-4'-O-methylDX, as a percentage of the administered dose, was 1.3-2 times higher than that of DX in the organs and 3 times higher in the tumor, which suggests an improved selectivity of the new analogue for the tumor compared with DX.

A differential interaction of doxorubicin and daunorubicin with human serum proteins.

The results of a comparative investigation on the interaction of doxorubicin (adriamycin) and daunorubicin with serum proteins are reported. Whereas a strong interaction occurs in vitro between doxorubicin and human serum proteins, no appreciable binding to proteins could be detected for daunorubicin under similar experimental conditions. Since the protein-bound drug is only partially dissociated by physical procedures including gel-electrophoresis, column-chromatography and solvent extraction, the formation of a covalent bond is suggested. The doxorubicin binding to serum proteins is apparently nonselective for a class of proteins; it is strongly reduced in acid conditions and slightly dependent on the ionic strength. Two tentative reaction mechanisms have been considered.