Drug time-dependent inhibition

Flurbiprofen and indomethacin, which comprise the third class of inhibitors, cause a slow, time-dependent inhibition of COX-1 and COX-2, apparently via formation of a salt bridge between a carboxylate on the drug and Arg , which lies in the tunnel. 

Methotrexate is a valuable drug that is commonly used in the treatment of inflammatory diseases, autoimmune diseases, and proliferative dieases. Its true potency can only be realized by the proper, quantitative analysis of the time-dependent inhibition of DHFR by this compound. 

Atkinson, A., Kenny, J.R. and Grime, K. (2005) Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis. Drug Metabolism and Disposition, 33 (11), 1637—1647. 

Yamamoto, T., Suzuki, A. and Kohno, Y. (2004) High-throughput screening for the assessment of time-dependent inhibitions of new drug candidates on... 

Time-dependent inhibition should be examined. A 30-minute preincubation (i.e., with nicotinamide adenine dinucleotide phosphate (NADPH) enzyme, and drug candidate prior to addition of the probe substrate) is recommended. 

An in vitro examination of time-dependent inhibition of the major drug-metabolizing CYP enzymes should be considered essential for drug candidates. Time-dependent inhibition occurs when the inhibitory potential of a drug candidate increases as the enzyme is exposed to the inhibitor over time. This type of inhibition may occur by several potential mechanisms, including the following ... 

It is recommended that inhibition studies with intact hepatocytes be performed if inhibitory effects of a drug or drug candidate have been observed with rCYP or liver microsomes to allow a more accurate prediction of the extent of in vivo inhibitory effects. Time-dependent inhibition of P450 can also be studied using intact human hepatocytes.26 One precaution with the use of intact hepatocytes is to concurrently measure also cytotoxicity. As dead hepatocytes are not active in drug metabolism, without cytotoxicity information, cytotoxic drug concentrations could be interpreted as inhibitory concentrations. 

Time-dependent inhibition observed The inhibitor is a time-dependent inhibitor. In vivo studies will need to be performed to further define its drug-drug interaction potential. 

Masubuchi Y, Kawaguchi Y (2013) Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor. Biopharm Drug Dispos 34 423 30... 

Harrelson JP, Stamper BD, Chapman JD, Goodlett DR, Nelson SD (2012) Covalent modifieation and time-dependent inhibition of human CYP2E1 by the meta-isomcT of aeetaminophen. Drug Metab Dispos 40 1460 1465... 

The drug SC-558 acts by a fourth mechanism, specifically inhibiting COX-2. It is a weak competitive inhibitor of COX-1 but inhibits COX-2 in a slow, time-dependent process. Specific COX-2 inhibitors will likely be the drugs of the future because they selectively block the inflammation mediated by COX-2, without the potential for stomach lesions and renal toxicity that arise from COX-1 inhibition. 

McGinnity, D.F., Berry, A.J., Kenny J.R., Grime, K. and Riley, R.J. (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metabolism and Disposition, 34 (8), 1291-1300. 

Short term treatment with TPA sensitized human 2008 ovarian carcinoma cells to cis-platin. This sensitization disappeared completely by seven hours after treatment, indicating that not inhibition, but activation of PKC sensitizes 2008 cells to the antiproliferative activity of cis-platin (Isonishi et al., 1990). Pretreatment of HeLa cells with TPA or PdBu caused a 9-fold increase in cellular sensitivity to cis-platin and 2.5-fold to melphalan, but had now effect on the antiproliferative activity of bleomycin, adriamycin, vincristine, or mitomycin C. The sensitization of HeLa cells by TPA was associated with a 6-fold stimulation of PKC activation and a concentration- and time-dependent increase in cellular platinum content. (Basu et al. 1990). PKC activity was found to be decreased significantly in cis-platin-resistant human small cell lung H69/CP cancer cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cis-platin. A modest decrease in PKC activity was also observed in etoposide-resistant H69 cells but not in taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells (Basu et al., 1996), indicating that reduced PKC activity leads to decreased sensitivity in this system. 

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