The plasma disposition kinetics and tissue distribution of platinum was evaluated following intravenous bolus administration to CD1 immune-competent mice of cisplatin, cisplatin conjugated to anti-CEA monoclonal antibody A5B7 via a carboxymethyl dextran (CMdextran) carrier molecule, and cisplatin coupled to the CMdextran in the absence of antibody. In addition, the in vivo characteristics of 125I-labeled A5B7 were compared with and without conjugation to CMdextran. Conjugation of cisplatin [clearance (CL = 0.62 mL/min/g, volume of distribution at steady-state (Vdss) = 16 mL/g] to CMdextran restricted its tissue distribution (Vdss = 0.43 mL/g) and reduced its systemic clearance (CL = 0.055 mL/min/g). Subsequent conjugation of the complex to A5B7 further reduced both its distribution (Vdss = 0.20 mL/g) and clearance (CL = 0.016 mL/min/g). Clearance of A5B7 (CL = 0.002 mL/min/g) was increased by conjugation to CMdextran (CL = 0.014 mL/min/g); tissue distribution was unchanged. A5B7-CMdextran-cisplatin was relatively stable in plasma and other tissues, except the liver. The extent of distribution of platinum into tissues (lung, liver, muscle, kidney) was markedly influenced by conjugation, with the influence being greatest for unmodified cisplatin and least for the A5B7-CMdextran conjugate. However, the time courses of tissue distribution, expressed in mean residence time scales, were similar, implying a common mechanism controlling tissue uptake.

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The glutathione transferases (GSTs) form a group of enzymes responsible for a wide range of molecular detoxications. The photoaffinity label S-(2-nitro-4-azidophenyl)glutathione was used to study the hydrophobic region of the active site of the rat liver GST 1-1 and 2-2 isoenzymes (class Alpha) as well as the rat class-Mu GST 3-3. Photoaffinity labelling was carried out using a version of S-(2-nitro-4-azidophenyl)glutathione tritiated in the arylazido ring. The labelling occurred with higher levels of radioisotope incorporation for the Mu than the Alpha families. Taking rat GST 3-3, 1.18 (+/- 0.05) mol of radiolabel from S-(2-nitro-4-azidophenyl)glutathione was incorporated per mol of dimeric enzyme, which could be blocked by the presence of the strong competitive inhibitor, S-tritylglutathione (Ki = 1.4 x 10(-7) M). Radiolabelling of the protein paralleled the loss of enzyme activity. Photoaffinity labelling by tritiated S-(2-nitro-4-azidophenyl)glutathione on a preparative scale (in the presence and absence of S-tritylglutathione) followed by tryptic digestion and purification of the labelled peptides indicated that GST 3-3 was specifically photolabelled; the labelled peptides were sequenced. Similarly, preparative photoaffinity labelling by S-(2-nitro-4-azidophenyl)glutathione of the rat liver 1-1 isoenzyme, the human GST A1-1 and the human-rat chimaeric GST, H1R1/1, was carried out with subsequent sequencing of radiolabelled h.p.l.c.-purified tryptic peptides. The results were interpreted by means of molecular-graphics analysis to locate photoaffinity-labelled peptides using the X-ray-crystallographic co-ordinates of rat GST 3-3 and human GST A1-1. The molecular-graphical analysis indicated that the labelled peptides are located within the immediate vicinity of the region occupied by S-substituted glutathione derivatives bound in the active-site cavity of the GSTs investigated.

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