On the basis of the Isolndole formation mechanism In the o-phthalaldehyde/2-mercaptoethanol (OPA/2-ME) derivatization of primary amines and the structure-stability relationships for Isolndoles, an Improved fluorogenic reagent, naphthalene-2,3-dlcarboxaldehyde (NDA) In the presence of cyanide ion (CN ), has been developed. Reaction of NDA/ CN' with primary amines In aqueous media results In the formation of -substKuted 1-cyanobenz[/]lsoindole (CBI) derivatives which have significantly Improved stability compared to the corresponding OPA/2-ME derivatives (for glycine greater than 50-fold Improvement was realized) and have high quantum efficiencies for fluorescence ( , = 0.54 In 60% aqueous acetonitrile for the CBI--propylamine derivative) In solvent systems commonly used In liquid chromatography. Parameters In the NDA/CN' derivatization of alanine are defined (l.e., pH and the reagent component concentrations) and used In the development of a labeling procedure for amino acid mixtures. Gradient elution fractionation of 18 CBI-amino acid derivatives was accomplished In 60 min and permitted detection limits of less than 200 fmol Injected (excitation 246 nm) or 3 pmol Injected (excitation 420 nm). The utility of the reagent In assaying amino acid mixtures resulting from the enzymatic hydrolysis of the peptides Met-enkephalln and glucagon Is demonstrated.

Plasma concentrations of cisplatin, total platinum, and total filterable platinum were monitored in 24 patients after either 50 or 100 mg/m2 of cisplatin by rapid intravenous injection. Half the patients at each dose were pretreated with mannitol. Total platinum levels declined in a triphasic fashion with a terminal half-life (t1/2)greater than or equal to 24 hr. Both total filterable platinum and cisplatin levels declined in a monophasic manner and exhibited t1/2 of 0.3 to 0.5 hr. The ratio of cisplatin to total filterable platinum in plasma remained constant (0.6 to 0.8) over the time period (2 hr) during which they could be detected, while the ratio of the plasma levels of cisplatin to total platinum decreased continuously from approximately 0.5 at 5 min to approximately 0.10 at 2 hr. Larger doses of cisplatin resulted in higher plasma levels of all three species monitored, and although the increases appeared somewhat less than proportional to dose, terminal plasma slopes were not dose dependent. Neither mannitol nor dose had an effect on the various species ratios, nor did mannitol appear to affect either plasma levels or terminal plasma decline.

The relative ability of the antiestrogen, tamoxifen, and its monohydroxy and desmethyl metabolites to displace tritiated estradiol from estrogen receptors isolated from human breast carcinoma was determined. 4-Hydroxytamoxifen binds to the estrogen receptor with affinity equal to estradiol, and with 25-50 times higher affinity than does tamoxifen. Desmethyltamoxifen binds to the estrogen receptor with less than 1 per cent of the affinity of tamoxifen. Blood level determination of tamoxifen species in breast cancer patients receiving the drug indicated that after 3 weeks of therapy, desmethyltamoxifen levels were 1.2-1.8 times greater than tamoxifen levels and 4-hydroxytamoxifen levels were 2-18 per cent of parent drug concentrations. Thus, because of its high affinity for the estrogen receptor, the 4-hydroxy metabolite may play a significant antiestrogenic role following tamoxifen therapy, despite its low relative abundance. Desmethyltamoxifen, on the other hand, may have only minor importance as an anti-estrogenic agent following tamoxifen treatment, due to its poor affinity for the estrogen receptor coupled with blood levels that are at most 75 per cent greater than tamoxifen levels at steady state.

No abstract