Liver enzyme induction and

Isojarvi JI, Pakarinen AJ, Rautio A, Pelkonen O, Myllyla VV. Liver enzyme induction and serum lipid levels after replacement of carbamazepine with oxcarbazepine. Epilepsia 1994 35(6) 1217-20. 

Environmental factors. Examples of these are co-administration of other drugs, which can affect the rate and extent of drug metabolism. This can become literally a matter of life and death as a number of potentially fatal drug interactions involve liver enzyme induction and competition for drug-metabolism enzymes. 

The above narrative exemplifies a successful lead identification story, ensued by a successful lead optimization that led to the discovery of the FDA-approved drug vorapaxar. The original hit (2) was a racemic synthetic analog of himbacine, a natural product that has no thrombin receptor activity. Had we made this analog in the absolute chirality of himbacine, we would have missed the hit, since the thrombin receptor antagonist activity is exclusive to the unnatural e t-him-bacine series. The lead optimization efforts encountered several obstacles, as highlighted by the discontinuation of two recommended candidates. Within the project, we had to return several times to secondary lead generation and optimization in order to address the liabilities such as liver enzyme induction and sub-optimal mass balance that we encountered in the development candidates. 

Agarwal et al. 1978), the quantification of these specific enzymes may indicate that exposure to endosulfan has occurred. Blood tests, such as decay curves for aminopyrine in plasma, which are semiquantitative indices of liver enzyme induction, have been used successfully in the past to demonstrate enzyme induction in pesticide-exposed workers. Because numerous chemicals found at hazardous waste sites also induce these hepatic enzymes, these measurements are not specific for endosulfan exposure. However, measurements of enzyme activity, together with the detection of the parent compound or its metabolites in tissue or excreta, can be useful indicators of exposure. All of these potential biomarkers require further verification in epidemiological studies. Further studies with focus on the development of methods to separate and measure the estrogenicity of endosulfan in in vitro assays would be valuable since these assays are more sensitive and discriminative than other conventional biomarkers. Preliminary results have been presented by Sonnenschein et al. (1995). 

Lindahl-Kiessling, K., Karlberg, I. and Olofsson, A.M. (1989). Induction of sister-chromatid exchanges by direct and indirect mutagens in human lymphocytes, co-cultured with intact rat liver cells Effect of enzyme induction and preservation of the liver cells by freezing in liquid nitrogen. Mutat. Res. 211 77-87. 

Plummer JL, de la Hall P, Isley AH, et al. 1990. Influence of enzyme induction and exposure profile on liver injury due to chlorinated hydrocarbon inhalation. Pharmacol Toxicol 67 329-335. 

Dannan GA, Sleight SD, Fraker PJ, et al. 1982. Liver microsomal enzyme induction and toxicity studies with 2,4,5,3, 4 -pentabromobiphenyl. Toxicol Appl Phannacol 64 187-203. 

Madsen C, Larsen JC. 1989. Relative toxicity of chlorinated dibenzo-para-dioxins, and dibenzofiirans measured by thymus weight and liver-enzyme induction in perinatally dosed rats 2,3,7,8-TCDD, 2,3,4,7,8-PCDF, 1,2,3,7,8-PCDD. Chemosphere 18 955-966. 

In a subacute study, both male and female rats were fed diets containing octachlorostyrene at 0.5, 5.0, 50, and 500 mg kg for 28 days. Histological changes were observed in the liver and thyroid of rats exposed to doses equal to or greater than 5 mgkg. Hepatic microsomal enzyme induction and liver hypertrophy were observed in the two highest dose groups. At 500 mg kg there was an increase in... 

The hepatic mechanistic studies in the rat were thus of great value to show that the probable mechanism exists for PBO to cause such thyroid effects in the ral as a consequence of its potent microsomal enzyme-inducing activity. The fact that PBO showed a closely comparable profile to the archetypal inducer phe nobar bit one, which also induces increased thyroid activity, serves only to reinforce the likelihood that this is a classic secondary mechanism. The primary effect of both xcnobiotics is inextricably linked to their biological property of liver enzyme induction. This perturbation in turn leads to remote secondary effects on the thyroid. By recognizing and understanding this mechanism it may be appreciated that the levels of PBO to which humans might be exposed are more than 1000 times below the threshold for any effect in the liver. In the absence of any primary hepatic effect there can be no risk (o humans of any secondary (thyroidal) effect, to which they are in any case significantly less sensitive to than the rat. 

---