Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuronidation: Lorazepam, Oxazepam, Naloxone, and Zidovudine

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is less well established for substrates of UDP-glucuronosyltransferases (UGT) than for cytochrome P450 (CYP) metabolized drugs and more verification of simulations is necessary to increase confidence. To address specific challenges of UGT substrates, we developed PBPK models for four drugs cleared majorly via glucuronidation (lorazepam, oxazepam, naloxone, and zidovudine). In vitro to in vivo scaling of intrinsic clearance generated with co-cultured human hepatocytes was applied for hepatic metabolism and extra-hepatic clearance was extrapolated based on relative expression of UGT isoforms in the liver, kidney, and intestine. Non-metabolic clearance and the contributions of individual UGT isoforms to glucuronidation were based on in vitro and in vivo studies taken from the literature and simulations were verified and evaluated with a broad set of clinical pharmacokinetic data. Model evaluation showed systemic clearance predictions within 1.5-fold for all drugs and all simulated parameters were within 2-fold of observed. However, during the verification step, top-down model fitting was necessary to adjust for under-prediction of zidovudine V SS and renal clearance and over estimation of intestinal first pass for lorazepam, oxazepam, and zidovudine. The impact of UGT2B15 polymorphisms on the pharmacokinetics of oxazepam and lorazepam was Electronic supplementary material The online version of this article (

PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5′-Diphospho-glucuronosyltransferase Substrates

“…Data for UGT1A1 expression in the GI tract are reasonably consistent across studies, and therefore PBPK modeling for UGT1A1 intestinal metabolism has a stronger foundation than for other UGTs (e.g., UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B17), for which existing expression data are less consistent ( Table 1 ). In the modeling work of Docci et al [ 23 ], initial predicted oral clearance based on IVIVE was within two-fold for lorazepam (substrate of UGT2B7 and UGT2B15), oxazepam (substrate of UGT1A9 and UGT2B15), and zidovudine (substrate of UGT2B7 and CYP3A4), but bioavailability was underestimated until Vmax values were scaled with an empirical factor of 0.25 to reduce the predicted first-pass metabolism in the gut. As additional intestinal expression data and modeling work becomes available, PBPK modeling for all the UGTs expressed in the GI tract will be strengthened by capitalizing on this systems biology approach.…”

“…5.1. Lorazepam (UGT2B7, UGT2B15), Oxazepam (UGT1A9, UGT2B15), Naloxone (UGT2B7), and Zidovudine (UGT2B7, CYP3A4) Recently, Docci et al [23] provided a detailed description of PBPK model construction for four UGT substrates: benzodiazepines lorazepam (UGT2B7, UGT2B15) and oxazepam (UGT1A9, UGT2B15), the antiretroviral zidovudine (UGT2B7, CYP3A4), and the opioid antagonist naloxone (UGT2B7). Docci followed a systematic model building approach, leveraging intrinsic clearance measurements made with HepatoPac ® [62], which is a micropatterned coculture of primary human hepatocytes with mouse fibroblasts.…”

“…Challenges for UGT IVIVE also include organ-dependent specificity as well as clinical relevance for polymorphisms [ 21 , 22 ]. Nonetheless, recent work has demonstrated the potential utility of PBPK modeling to predict UGT-mediated intestinal metabolism through an IVIVE approach [ 16 , 23 ] and a focus on clinical absorption, distribution, metabolism and excretion (ADME) and PK data [ 24 ].…”

Simultaneous Quantification of Propylthiouracil and Its N-β-d Glucuronide by HPLC-MS/MS: Application to a Metabolic Study

“…The results showed that PTU had a good affinity to UGT1A9. Based on the result of these in vitro experiments, a physiologically-based pharmacokinetic model of PTU could be developed and validated by clinical data, enabling an accurate prediction on its hepatotoxicity and the risk of drug-drug interaction [31][32][33][34].…”

Characterization of Hepatic UDP-Glucuronosyltransferase Enzyme Abundance-Activity Correlations and Population Variability Using a Proteomics Approach and Comparison with Cytochrome P450 Enzymes

“…The IVIVE approach is less well established for UGTs (Jones et al, 2015) for which (compared with CYPs) fewer enzyme-selective probe substrates have been studied and over a shorter period of time. Recently, Docci et al developed PBPK models for four UGT substrates, using available clinical data to overcome gaps in IVIVE (Docci et al, 2020). Their work also highlighted gaps and uncertainties in UGT abundance data which currently limit IVIVE and PBPK modelling for UGT substrates.…”