Induction potential

Determine the drug interaction potential when concurrent medications are administered, as well as food interaction, assess the enzyme induction potential, and assess the need for therapeutic drug monitoring during efficacy testing. 

Preliminary evidence suggests that dispersants have little effect in enhancing the inductive potential of spilled oil. Dispersed crude was no more effective than crude alone in AHH induction (Table VI)... 

Jones, S.A., Moore, L.B., Wisely, G.B. and Kliewer, S.A. (2002) Use of in vitro pregnane X receptor assays to assess CYP3A4 induction potential of drug candidates. Methods in Enzymology, 357, 161-170. 

Persson, KP., Ekehed, S., Otter, C., Lutz, E.S., McPheaL J., Masimirembwa, C.M. and Andersson, T.B. (2006) Evaluation of human liver slices and reporter gene assays as systems for predicting the cytochrome p450 induction potential of drugs in vivo in humans. Pharmaceutical Research, 23, 56-69. 

Collective evidence indicates that mGluR play multiple roles in synaptic plasticity. LTP induction, potentiation of NMD A receptor activity in CA1 neurons, and hippocampal NMDA receptor-dependent LTD involve mGlu receptors. 

In comparison to N- and C-caps, position-independent templates potentially offer significant advantages. Incorporated at internal positions, these templates are supposed to transmit the conformational information along the helix axis towards both termini of the peptide. If the helix induction potential is comparable to that observed for N- and C-caps, position-independent templates at internal positions might stabilize up to five consecutive a-helical turns, or peptides with 18 amino acids.202... 

HIT-linked peptides proved to be valuable tools to assess the a-helix induction potential of HIT-1. CD measurements revealed that HIT-1 has a high a-helix inducing potential at the N-terminus. Incorporated at internal positions, HIT-1 proved to be a moderate a-helix inducer and it strongly initiated the formation of 310-helical conformations once incorporated at the C-terminus. Based on these results, and for reasons of chemical stability, we replaced the (/ )-serine linker by the more rigid and a-helix compatible (/ )-a-methylserine analogue.203... 

Fent, K. (2001) Fish cell lines as versatile tools in ecotoxicology assessment of cytotoxicity, cytochrome P4501A induction potential and estrogenic activity of chemicals and environmental samples,... 

Induction of CYP expression by xenobiotics has been reported in mainly three ways (1) induction potential (fold induction over control), (2) EC50 (effective concentration for 50% maximal induction), and (3) potency index (the ratio of induction response of the test compound compared to that of a gold standard). In our laboratory, we have defined CYP induction as a potency index or a percentage of a classic inducer rather than as fold increase over a control (induction potential). The reason for this is twofold. First, the basal levels of some CYPs may be low and therefore difficult to accurately quantitate. Second, we, and others, have found that basal CYP levels in culture may be highly... 

Surry DD, Meneses-Lorente G, Heavans R, et al. Rapid determination of rat hepatocyte mRNA induction potential using oligonucleotide probes for CYP1A1, 1A2, 3A and 4A1. Xenobiotica 2000 30 441 156. 

Li AP, Reith MK, Rasmussen A, et al. Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics evaluation of rifampin, rifapentine and rifabutin. Chem Biol Interact 1997 107 17-30. 

Simultaneous administration of a mixture of substrates of CYP enzymes in one study (i.e., a cocktail approach ) in human volunteers is another way to valuate a drug s inhibition or induction potential (35), provided that the study is designed properly and the following factors are present (1) the substrates are specific for individual CYP enzymes, (2) there are no interactions among these substrates, and (3) the study is conducted in a sufficient number of subjects. Negative results from a cocktail study can eliminate the need for further evaluation of particular CYP enzymes. However, positive results can indicate the need for further in vivo evaluation to provide quantitative exposure changes (such as AUC and Cmax), if the initial evaluation only assessed the changes in the urinary parent to metabolite ratios. 

Table 2 Nuclear receptors (NR) for enzyme inducers. Enzyme inducers are now known to act as ligands to nuclear receptors, leading to gene activation and increased synthesis of the enzyme. Affinity of inducers to die receptors is now known to be responsible for the differential induction potential and can explain die observed species-differences in induction. The receptors tabulated are aryl hydrocarbon receptors (AhR), constituitively androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR). The isoforms in bold type are the major isoform regulated by the corresponding receptors.

Enzyme induction assays are generally performed for the evaluation of the effects of the substance tested on P450 induction. For animal studies, liver enlargement (e.g. liver weight gain) as well as increases in P450 activities after a relevant treatment period (e.g. 14 days) are used as endpoints for enzyme induction potential. 

The procedures described with human hepatocytes represent the gold standard for the assessment of human induction potential of xenobiotics. As of now, there appears to be no evidence of known human P450 inducers which are not inducers in vitro using the assay described. The following are additional issues critical to the performance of the assay ... 

The above-mentioned experimental systems are more convenient than freshly isolated hepatocytes. However, as of this writing, results obtained with these alternative systems need to be confirmed with those from freshly isolated hepatocytes to assess the true induction human enzyme induction potential. 

Li AP, Reith MK, Rasmussen A et al. (1997) In vitro evaluation of drug-drug interaction potential A comparison of rifampin, rifapentine, and rifabutin in cytochrome P450 3A induction potential in primary human hepatocytes. Chemico-Biological Interactions 107 17-30... 

Cytotoxic compounds Induction effects can be masked by the decrease of cell viability, as most induction assays quantify substrate metabolism in situ (in the same cell culture plate that the cells are cultured) and assume that there is no change in cell number. Cytotoxicity evaluation therefore should always be performed concurrently with induction studies. In the presence of cytotoxicity, activity should be corrected by the viability for comparison with negative control activity to assess induction potential. 

Drugs with P450 induction potential in humans are shown in Table 5.10. It is interesting to note that most of these inducers are also found to have clinically significant hepatotoxicity. 

Evaluation of induction potential of the drug or drug candidate in question for the inducible human drug-metabolizing enzymes will allow the assessment of potential interactions with drugs that are substrates of the induced enzymes. 

Roymans D, Annaert P, Van Houdt J, et al. Expression and induction potential of cytochromes P450 in human cryopreserved hepatocytes. Drug Metab Disp. 2005 33 1004-1016. 

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