Alterations in the C-9 side chain of the anthracycline antibiotics, adriamycin and daunorubicin, have a profound effect on antibiotic uptake and accumulation by cultured L1210 cells. The degree of inhibition of DNA and RNA biosynthesis in the L1210 cells is directly related to the cellular uptake and accumulation of the drug analogues. Polar drug metabolites, daunorubicinol and adriamycinol, retain inhibitory activity against nucleic acid metabolism but have a decreased membrane binding and permeability. Cellular uptake and accumulation of the C-9 analogues are inversely related to drug polarity. We propose that the polarity of the anthracycline analogues contributes heavily to the differences in therapeutic index and in vivo activity through fundamental effects on membrane permeability, metabolism, and macromolecular binding.

In 38 adriamycin experiments and 4 daunorubicin experiments, radioimmunoassay readily and reproducibly detects and estimates these drugs and immunologically similar metabolites in patients' plasma and urine to at least 120 hr after dosing without interference by concurrent medication. The plasma drug decay follows first-order kinetics in a triphasic pattern. Radioimmunoassay and fluorescence assay show similar decay up to 4 hr but diverge at that point with the fluorescence assay yielding higher values. Pharmocokinetic differences are amplified in patients with liver dysfunction and may be caused by fluorescent drug metabolites not sensitive to radioimmunoassay or nonspecific fluorescent materials. The radioimmunoassay offers the capability to measure adriamycin and daunorubicin in clinical settings in which fluorescence assay is not available.