In a study of toxicokinetic interactions of human-exposure xenobiotics, the effects of ethanol cotreatment on the pharmacokinetics of the environmental carcinogen, N-nitrosodimethylamine (NDMA), were measured in male patas monkeys. Ethanol, given orally before i.v. NDMA or concur- rently with an i.g. dose, resulted in major (10- to 50-fold) increases in the total tissue exposure (area under the blood concentration versus time curves) and in duration of exposure (mean residence time) to the carcinogen. Isopropanol given before NDMA, also increased these parame- ters in association with persistence of isopropanol and its metabolic product acetone. While no NDMA was detected in expired air, trace amounts were found in urine. Ethanol and isopropanol pretreatment increased the maximum urinary NMDA concentration 15- to 50-fold and the percent of the dose excreted in the urine by 100- to 800-fold. These striking effects of ethanol and isopropanol are interpreted as due to competitive inhibition of clearance of NDMA cytochrome P450 2E1 in liver, and may help explain the contribution of alcoholic beverage use to human cancer risk. A study has been initiated of the transplacental passage and fetal DNA adduct formation by chemotherapeutic drugs. Since DNA adducts of cisplatin and carboplatin are persistent in human tissues many months after therapy, harmful effects on the fetus may be of concern when these chemicals must be administered for treatment of malignancies during pregnancy.
