A total of 26 metabolites of amiodarone were detected in the investigated in vitro and in vivo matrices. The suspected ortho-diquinone metabolite was one of them. The formation of the same might be an added reason for the hepatotoxicity shown by the drug.
Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug-metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index drugs are particularly vulnerable to undesired pharmacodynamics (PD) because of the changes in drug PK in disease states. However, systematic clinical evaluation of disease effect on drug PK and PD is not always possible because of the complexity or the cost of clinical studies. Physiologically based PK (PBPK) modeling is emerging as an alternate method to extrapolate drug PK from the healthy population to disease states. These models require information on the effect of disease condition on the activity or tissue abundance of DMET proteins. Although immunoquantification-based abundance data were available in the literature for a limited number of DMET proteins, the emergence of mass spectrometry-based quantitative proteomics as a sensitive, robust, and high-throughput tool has allowed a rapid increase in data availability on tissue DMET abundance in healthy versus disease states, especially in liver tissue. Here, we summarize these data including the available immunoquantification or mRNA levels of DMET proteins (healthy vs disease states) in extrahepatic tissue and discuss the potential applications of DMET abundance data in enhancing the capability of PBPK modeling in predicting drug disposition across disease states. Successful examples of PBPK modeling that integrate differences in DMET proteins between healthy and disease states are discussed.
Ortho Tri-Cyclen, a two-drug cocktail comprised of ethinylestradiol and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported. Hence, detailed biotransformation and reaction phenotyping studies of NGMN with recombinant cytochrome P450 (P450), recombinant uridine 5'-diphospho-glucuronosyltransferases, and human liver microsomes in the presence and absence of selective P450 inhibitors were conducted. It was found that CYP3A4 plays a key role in NGMN metabolism with a fraction metabolized () of 0.57. CYP2B6 and to an even lesser extent CYP2C9 were also observed to catalyze NGMN metabolism. Using this CYP3A4 value, the predicted plasma concentration versus time area under the curve (AUC) change in NGMN using a basic/mechanistic static model was found to be within 1.3-fold of the reported NGMN AUC changes for four modulators of CYP3A4. In addition to NGMN, we have also elucidated the biotransformation of norgestrel (NG), a downstream norgestimate and NGMN metabolite, and found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combined value of 1. The data presented in this paper will lead to better understanding and management of NGMN-based drug-drug interactions when norgestimate is coadministered with CYP3A4 modulators.
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