PURPOSE: The hepatic extraction of a novel antiarrhythmic, RSD1070, was investigated to test the hypothesis that the poor bioavailability observed in rats is due to high hepatic metabolism. METHODS: The pharmacokinetics of RSD1070 was examined in rats (n=8) and its metabolism was investigated using pooled rat hepatic microsomes. The free fraction in plasma and microsomal matrices was determined by equilibrium dialysis. Hepatic extraction was predicted by scaling-up of the microsomal kinetic data using the well-stirred liver model. RESULTS: RSD1070 demonstrated tri-exponential decay following single iv bolus administration of a dose of 12 mg/kg. RSD1070 exhibited a rapid elimination, t1/2 of 25 +/- 8 min and a CL(tot) of 71 +/- 9 mL/min/kg. Renal clearance based on 24 h urinary recovery was determined to be insignificant (<< 1% of CL(tot)). A Michaelis-Menten model described the elimination of RSD1070 with a K(m) of 0.45 microg/mL and Vmax of 2.81 microg/min/mg microsomal protein. Taking the V(max)/K(m) ratio (CL(int)) as the basis for scaling, the data from the microsomal kinetic studies (75 mL/min/kg) closely approximated the apparent CL(tot). In the scale-up of the in vitro CL(int), plasma free fraction (1.5%) and microsomal free fraction (15%) were determined and incorporated into the well-stirred liver model. CONCLUSION: RSD1070 is a high hepatic extraction compound (E = 0.94) with a predicted CL(h) value that accounted for the CL(tot) observed in rats.

Animals↗

PubMedDate not supplied

Regulatory effect of steroid hormones on the growth of human malignant melanoma.

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Adolescent↗

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Incidence of estrogen receptor in benign nevi and human malignant melanoma.

This study was performed as an initial step to evaluate the possible effects of steroid hormones on benign nevi. Cytoplasmic receptors for estrogen were found in nine (41%) of 21 benign nevi from melanoma patients. Ten (37%) of 27 melanoma tumor tissues also had receptor for estrogen. Benign nevi from 17 normal persons had no estrogen receptor activity. The similar incidence of estrogen receptor in benign nevi from melanoma patients and in melanoma tissue itself, compared with the absence of receptor in benign nevi from a normal population, suggest that steroid hormones such as estrogen may represent a molecular alteration associated with a potential pathophysiologic transformation of a benign nevus to its malignant counterpart.

Cytoplasm↗

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The effects of ketoconazole on the human fibrosarcoma cell line HT-1080.

In light of the reported cytotoxic effects of the antifungal agent ketoconazole on several malignant cell lines, we investigated the in vitro and in vivo effects of this drug on the human fibrosarcoma cell line HT-1080. Utilizing an anchorage dependent in vitro assay, we demonstrated an IC90 of 10.0 micrograms/ml at 72 hours and a decreasing IC90 with increasing exposure (IC90 = 6.2 micrograms/ml at 12 days). In vivo investigation utilizing the subcutaneous growth of this tumor in athymic mice and the oral, subcutaneous or intraperitoneal administration of ketoconazole at doses of 5-50 mg/kg/day demonstrated no consistent activity. Ketoconazole appears to have significant in vitro activity for HT-1080 but this does not translate into significant in vivo activity and its clinical relevance in sarcoma remains uncertain.

Administration, Oral↗

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The expression of C-myb in human metastatic melanoma cell lines and specimens.

The rapidly increasing incidence of malignant melanoma and lack of effective systemic therapy for advanced disease has given rise to the need for new approaches. The suggestion that c-myb may be an important gene in the control of melanoma proliferation prompted the exploration of its expression in several metastatic melanoma cell lines and specimens. Initial Northem hybridization showed undetectable expression of c-myb in the cell lines, although it was very strongly expressed in the K-562 cell line. Therefore, c-myb expression was examined utilizing primers and RT-PCR on the five melanoma cell lines and thirty-two metastatic melanoma specimens. There was very low expression in the two cell lines (UISO Mel-1 and 3) that were nontumorigenic, whereas there was a 10 fold increase in expression in the tumorigenic cell lines. In the metastatic specimens the expression varied by over 100 fold between the lowest and highest specimens. The expression of c-myb in tumor specimens was in general greater than matched normal specimens, save for skin which had moderate expression. In general, there did not appear to be any correlation between the clinical characteristics of the various specimens and the amount of c-myb expression. However, females with lymph node metastases had somewhat lower expression than males. The fact that significant melanoma specimens have altered expression of c-myb, coupled with the previous inhibition of melanoma growth by antisense c-myb, suggests that there may be a potential role for c-myb antisense therapy in the treatment of this tumor.

Female↗