The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

Abstract

Major circulating drug metabolites can be as important as the drugs themselves in efficacy and safety, so establishing methods whereby exposure to major metabolites following administration of parent drug can be predicted is important. In this study, imipramine, a tricyclic antidepressant, and its major metabolite desipramine were selected as a model system to develop metabolite prediction methods. Imipramine undergoes N-demethylation to form the active metabolite desipramine, and both imipramine and desipramine are converted to hydroxylated metabolites by the polymorphic enzyme CYP2D6. The objective of the present study is to determine whether the human pharmacokinetics of desipramine following dosing of imipramine can be predicted using static and dynamic physiologically-based pharmacokinetic (PBPK) models from in vitro input data for CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) populations. The intrinsic metabolic clearances of parent drug and metabolite were estimated using human liver microsomes (CYP2D6 PM and EM) and hepatocytes. Passive diffusion clearance of desipramine, used in the estimation of availability of the metabolite, was predicted from passive permeability and hepatocyte surface area. The predicted area under the curve (AUC m /AUC p ) of desipramine/imipramine was 12-to 20-fold higher in PM compared with EM subjects following i.v. or oral doses of imipramine using the static model. Moreover, the PBPK model was able to recover simultaneously plasma profiles of imipramine and desipramine in populations with different phenotypes of CYP2D6. This example suggested that mechanistic PBPK modeling combined with information obtained from in vitro studies can provide quantitative solutions to predict in vivo pharmacokinetics of drugs and major metabolites in a target human population.

Metabolites of alectinib in human: their identification and pharmacological activity

“…In general, hepatocytes and liver subcellular fractions are commonly known and predictive approaches to elucidate these steps have been published [8, 9, 10, 11], however, these in vitro approaches have proved insufficient to reflect the in vivo profile and the main metabolic pathway in human in the case of such as slow metabolite turnover rate, and extrahepatic metabolism. Therefore, a human ADME study is essential to determine via mass balance the elimination pathways of an administered drug and give a metabolite profile definitively in human.…”

Exploring PTDH–P450BM3 Variants for the Synthesis of Drug Metabolites

“…Many minor metabolites were formed by LVQVS as well. In the liver, imipramine is converted by several P450 isoenzymes (e.g., 1A2, 2D6, 3A4, and 2C9) into the active metabolites desipramine (IMI M1) and 2‐hydroxydesipramine …”

“…In the liver,i mipramine is converted by severalP 450 isoenzymes (e.g.,1 A2, 2D6, 3A4, and 2C9) into the active metabolites desipramine (IMI M1) and 2-hydroxydesipramine. [68][69][70] The reverset ranscriptasei nhibitor nevirapine (m/z 267.124 [M+ +H] + )w as only converted (> 3%)b yt he mutantL VQVS, and hydroxylation of the alkyl chain occurred to form 12-hydroxynevirapine (m/z 283.12[ M+ +H] + ;N EV M1) on the basis of the fragmentation pattern. This is one of fivem ain productsi n human metabolism and is formed by P450 3A4 and 2D6.…”

Prediction of Losartan-Active Carboxylic Acid Metabolite Exposure Following Losartan Administration Using Static and Physiologically Based Pharmacokinetic Models

“…27 We have previously examined this method coupled with static and dynamic PBPK modeling using midazolam and imipramine as test compounds. 5,6 These are examples in which both parent drugs and their metabolites are primarily eliminated by metabolism pathways. Prediction of in vivo PK of drugs that are transporter substrates remains an important challenge during drug discovery and development.…”

“…In our previous studies, a method to project metabolite/parent AUC ratios and pharmacokinetics (PK) of drug metabolites using in vitro drug metabolism data coupled with static and dynamic physiologically based pharmacokinetic (PBPK) modeling was examined and established using midazolam, imipramine, and their primary metabolites as test compounds. 5,6 In attempting to employ this method to other drug and metabolite pairs wherein overall clearance pathways are more complex, losartan and its active metabolite carboxylosartan were investigated. Losartan is a selective, competitive, reversible angiotensin II receptor antagonist for the treatment of hypertension.…”