Citation: Bui, D.; McWilliams, L.A.; Wu, L.; Zhou, H.; Wong, S.J.; You, M.; Chow, D.S.-L.; Singh, R.; Hu, M. Pharmacokinetic Basis for Using Saliva Matrine Concentrations as a Clinical Compliance Monitoring in Antitumor B Chemoprevention Trials in Humans. Cancers 2023, 15, 89. https://doi.org/10.3390/ cancers15010089 Academic Editor: Nagi B. Kumar Received: 1 December 2022 Revised: 15 December 2022 Accepted: 19 December 2022 Published: 23 December 2022 Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Article Pharmacokinetic Basis for Using Saliva Matrine Concentrations as a Clinical Compliance Monitoring in Antitumor B Chemoprevention Trials in Humans Dinh Bui 1 , Lenora A. McWilliams 2,† , Lei Wu 1,† , Haiying Zhou 3 , Stuart J. Wong 4 , Ming You 5 , Diana S.-L. Chow 1 , Rashim Singh 1, * and Ming Hu 1, * 1 College of Pharmacy, University of Houston, Houston, TX 77204, USA 2 College of Nursing, University of Houston, Houston, TX 77204, USA 3 Simulations Plus Inc., Lancaster, CA 93534, USA 4 Department of Neoplastic Diseases, Medical College of Wisconsin, Milwaukee, WI 53226, USA 5 Houston Methodist, Houston, TX 77030, USA * Correspondence: rsingh3@central.uh.edu (R.S.); mhu@uh.edu (M.H.) † These authors contributed equally to this work. Simple Summary: This is the first human study using saliva samples for drug therapeutic moni- toring and patient compliance for a complex botanical extract (e.g., ATB) and reporting the rapid and extensive secretion of certain active compounds (matrine, dictamnine) to human saliva. Specifi- cally, matrine is among the compounds with the highest excretion ratio to saliva with the ratio of saliva/plasma of 6.4 ± 1.4 for C max and 4.8 ± 1.7 for AUC in healthy adults. The results were further analyzed through a population PK model and a PBPK model, and the compound tracer (e.g., Matr) could serve as a competitive biomarker that enable further development of the salivary secretion based PK/PD analysis. Matrine has demonstrated to be a promising compound to study the drug transport to saliva and a marker compound to follow patient compliance. Abstract: This study reports the first clinical evidence of significantly high secretion of matrine in a multi-component botanical (Antitumor B, ATB) into human saliva from the systemic circulation. This is of high clinical significance as matrine can be used as a monitoring tool during longitudinal clinical studies to overcome the key limitation of poor patient compliance often reported in cancer chemoprevention trials. Both matrine and dictamine were detected in the saliva and plasma samples but only matrine was quantifiable after the oral administration of ATB tablets (2400 mg) in 8 healthy volunteers. A significantly high saliva/plasma ratios for C max (6.5 ± 2.0) and AUC 0–24 (4.8 ± 2.0) of matrine suggested an active secretion in saliva probably due to entero-salivary recycling as evident from the long half-lives (t 1/2 plasma = 10.0 ± 2.8 h, t 1/2 saliva = 13.4 ± 6.9 h). The correlation between saliva and plasma levels of matrine was established using a population compartmental pharmacokinetic co-model. Moreover, a species-relevant PBPK model was developed to adequately describe the pharmacokinetic profiles of matrine in mouse, rat, and human. In conclusion, matrine saliva concentrations can be used as an excellent marker compound for mechanistic studies of active secretion of drugs from plasma to saliva as well as monitor the patient’s compliance to the treatment regimen in upcoming clinical trials of ATB. Keywords: cancer chemoprevention; OCT transporter; PBPK modeling; plasma-saliva correlation; entero-salivary recycling; pharmacokinetics; saliva excretion marker; patient compliance tracker 1. Introduction Antitumor B (ATB) or Zeng Sheng Ping is a botanical drug, consisting of water extract or powder of six plants: Sophora tonkinensis Gagnep., Polygonum bistorta L., Prunella vulgaris L., Sonchus brachyotus DC., Dictamnus dasycarpus Turcz., and Dioscorea bulbifera L (Table 1). Cancers 2023, 15, 89. https://doi.org/10.3390/cancers15010089 https://www.mdpi.com/journal/cancers