HALF-LIFE OF OXAZAPHOSPHORINES IN BIOLOGICAL-FLUIDS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (5) , 553-559
Abstract
[Cyclophosphamide is a widely used antineoplastic and immunosuppressive prodrug.] Plasma AUC [area under the concentration-time curve] and half-life values for cyclophosphamide were determined in rats manipulated to hydroxylate cyclophosphamide at different rates; plasma AUC and apparent half-life values for 2 pharmacologically important metabolites of cyclophosphamide, i.e., 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard, were also determined in these animals. Apparent plasma half-life values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard increased with an increase in plasma half-life values for cyclophosphamide. AUC values for cyclophosphamide increased approximately linearily with an increase in its plasma half-life but AUC values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard remained approximately constant with an increase in their respective apparent plasma half-life values. Given that the cytotoxic effects of cyclophosphamide are directly proportional to AUC values for 4-hdyroxycyclophosphamide/aldophosphamide and/or phosphoramide mustard, changes in the rate of cyclophosphamide hydroxylation will evidently not alter the systemic toxic and therapeutic responses to a given dose of cyclophosphamide. Actual half-life values for 4-hydroxycyclophosphamide/aldophosphamide and phosphoramide mustard after the i.v. infusion of these agents were also determined. A comparison of the actual plasma half-life values for cyclophosphamide (29 min), 4-hydroxycyclophosphamide/aldophosphamide (14 min) and phosphoramide mustard (14 min) with the apparent plasma half-life values obtained for 4-hydroxycyclophosphamide/aldophosphamide (34 min) and phosphoramide mustard (55 min) following cyclophosphamide administration suggests that the major determinant with regard to the apparent plasma half-life of 4-hydroxycyclophosphamide/aldophosphamide is its rate of formation whereas in the case of phosphoramide mustard, an additional determinant, perhaps efflux from the cell, is operative. Half-life values for 4-hydroxycyclophosphamide/aldophosphamide were also determined after addition of the agent to plasma or serum in vitro; the values obtained were about 1/2 those obtained in vivo following i.v. infusion. Concomitant with the disappearance of 4-hydroxycyclophosphamide/aldophosphamide was the appearance of phosphoramide mustard. The rate of conversion was markedly pH- and temperature-dependent; it did not decrease when boiled serum was used. Conversion was minimal when acid-soluble serum was used. Serum phosphate and bicarbonate levels were insufficient to account for catalysis of the conversion; enzymatically catalyzed conversion is suspected.

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