US EPA

2208306 

Book/Book Chapter 

Deuterium-labeled analogs as probes for the study of cyclophosphamide pharmacokinetics, teratogenesis and mutagenesis 

Winckler, K; Lo Turco Mortler, CM; Spielmann, H; Obe, G; Nau, H 

1987 

CRC Press 

Boca Raton, FL 

Pharmacokinetics in teratogenesis: Vol 2. Experimental aspects in vivo and in vitro 

2 

83-96 

English 

is a chapter of 4397376 Pharmacokinetics in teratogenesis. Vol. 2. Experimental aspects in vivo and in vitro

The use of deuterium-labeled analogs of cyclophosphamide (CPA) in studies on teratogenesis, mutagenesis, and antineoplastic potency of CPA from our own and other laboratories is evaluated in this chapter. In the series of experiments described mutagenic effects of CPA and deuterated analogs in vitro as well as pharmacokinetics and teratogenic effects in vivo are compared to elucidate the metabolic pathway(s) leading to the ultimate mutagenic and teratogenic metabolite(s) of CPA. Isotope effects were found for the 5,5-d,-analogue of CPA for mutagenicity in vitro and teratogenicity and pharmacokinetics in vivo, indicating the crucial importance of the metabolic step that results in the formation of acrolein and phosphoramide mustard (PAM). Deuterium substitutions at the C4 or-C6 position of the CPA molecule have no substantial influence on the activities of the drug. For the antineoplastic properties of CPA similar findings have been reported. 

Nau, H; Scott, WJ, Jr 

9780849368745