piperidines and Leukemia-L5178

Compounds that interact with opioid receptors are commonly used as analgesics. Opioid agonists vary in their potency and pharmacokinetic properties as well as in their affinity for distinct opioid receptors. The fentanyl opiate analogues are an important group of analgesics that interact with the mu opioid receptor. Remifentanil (GI87084) is a particularly interesting member of this group of opioids because its action is especially short in duration. This report examines the genetic toxicology of remifentanil. Remifentanil was not genotoxic in an Ames test, an in vitro chromosome aberration assay in Chinese hamster ovary cells, an in vivo micronucleus assay in rat erythrocytes, or an in vivo/in vitro unscheduled DNA synthesis assay in rat hepatocytes. In the in vitro L5178Y tk(+/-) mouse lymphoma assay, remifentanil produced a genotoxic response at dose levels >or=308 microg/mL only in the presence of rat liver S9 metabolic activation; primarily tiny and small mutant colonies were produced. This pattern of activity in a battery of genetic toxicology assays is not unique to remifentanil, but has also been observed for other pharmaceuticals, including the opioid fentanyl. A weight-of-evidence analysis, taking into consideration genotoxic mechanisms, in vivo results, and the conditions of clinical use, suggests remifentanil does not pose a genotoxic risk to patients.

Topics: Analgesics, Opioid; Animals; CHO Cells; Chromosome Aberrations; Cricetinae; DNA Repair; Erythrocytes; Female; Hepatocytes; Leukemia L5178; Liver Extracts; Male; Mice; Micronucleus Tests; Mutagenicity Tests; Piperidines; Rats; Rats, Wistar; Remifentanil; Salmonella typhimurium; Tumor Cells, Cultured

Large differences in induced cellular toxicity were observed in the presence or absence of a rat liver microsomal metabolizing system (S-9) during drug testing in the mouse lymphoma assay. After studying the fate of three drugs in this test system, several mechanisms were demonstrated whereby S-9 reduced cellular toxicity. For N-(4-hydroxyphenyl)retinamide (HPR), fenoctimine sulfate and methyl palmoxirate, the drug concentrations (EC50) in the presence of S-9 were, respectively, 11.5, 14.3 and 4.1 times the concentrations required to achieve comparable levels of toxicity in the absence of S-9. HPR was metabolized by the S-9 and sequestered in the microsomal membranes. This was associated with a marked reduction in the cellular accumulation of the drug. The reduced toxicity of fenoctimine sulfate in the presence of S-9 was associated with extensive biotransformation to polar metabolites. This was accompanied by a reduction of radioactivity associated with the cells from 5.7% to 0.4% of the administered drug. Methyl palmoxirate was rapidly converted to its acid, palmoxirate, by horse serum enzymes present in the treatment medium. This provides an example of metabolism by a test system component other than the S-9 or lymphoma cells. The reduced toxicity of this drug in the presence of S-9 was attributed to further metabolism of palmoxirate and a reduction of the proportion of total radioactivity associated with the cells from 3.1% to 0.4%. These results emphasize the need for pilot toxicity studies, especially when components of the test system are varied, to assess the effect of drug concentration on the toxic response.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biotransformation; Cell Division; Cell Line; Cells, Cultured; Epoxy Compounds; Ethers, Cyclic; Fenretinide; Leukemia L5178; Leukemia, Experimental; Male; Mice; Microsomes, Liver; Mutagenicity Tests; Mutagens; Piperidines; Propionates; Rats; Tretinoin

Six representatives of inorganic cyclic systems (NPAz2)2 NSOX(Az = aziridino, X = F, Az, Ph) and (NPAz2)2 NPAzR [R = Az, Morph (morpholino), Pyr (pyrrolidino)] show cytostatic activity in an in vitro screening system. The technique of the in vitro screening system used is described. L5178Y and Ehrlich ascites cells are grown as suspension cultures in concave-bottomed wells in microtiter test plates using serial dilutions of the drugs in the medium. The diameter of the cell sedimentation spots, which can be compared visually is taken to determine the lowest active dose. The results of this test correspond with the cytostatic activities observed in former in vivo experiments.

Topics: Animals; Aziridines; Azirines; Carcinoma, Ehrlich Tumor; Cell Division; Cell Line; Cell Survival; Drug Evaluation, Preclinical; Leukemia L5178; Morpholines; Piperidines; Pyrrolidines