Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Drug Metabolism and Pharmacokinetics
Published in: European Journal of Drug Metabolism and Pharmacokinetics 6/2017

01-12-2017 | Original Research Article

Observation of Clinically Relevant Drug Interaction in Chimeric Mice with Humanized Livers: The Case of Valproic Acid and Carbapenem Antibiotics

Authors: Eiko Suzuki, Kumiko Koyama, Daisuke Nakai, Ryoya Goda, Hiroshi Kuga, Kan Chiba

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 6/2017

Login to get access

Abstract

Background and Objective

Human in vitro and dog in vitro/in vivo researches indicate that the drug–drug interaction (DDI) of decreased plasma valproic acid (VPA) concentration by co-administration of carbapenem antibiotics is caused by inhibition of acylpeptide hydrolase (APEH)-mediated VPA acylglucuronide (VPA-G) hydrolysis by carbapenems. In this study, we investigated VPA disposition and APEH activities in TK-NOG chimeric mice, whose livers were highly replaced with human hepatocytes, to evaluate the utility of this animal model and the clinical relevance of the DDI mechanism.

Methods

VPA and VPA-G concentrations in plasma, urinary excretion of VPA-G and APEH activity in humanized livers were measured after co-administration of VPA with meropenem (MEPM) to chimeric mice.

Results

After co-administration with MEPM to the chimeric mice, plasma VPA concentration more rapidly decreased than without the co-administration. An increase in plasma AUC and urinary excretion of VPA-G was also observed. APEH activity in humanized livers was strongly inhibited even at 24 h after co-administration of MEPM to the chimeric mice.

Conclusion

The DDI of VPA with carbapenems was successfully observed in chimeric mice with humanized livers. The DDI was caused by long-lasting inhibition of hepatic APEH-mediated VPA-G hydrolysis by carbapenems, which strongly supports the APEH-mediated mechanism of the clinical DDI. This is the first example showing the usefulness of chimeric mice with humanized livers for evaluation of a DDI via non-cytochrome P450 enzyme.
Literature
1.
Jaiswal S, Sharma A, Shukla M, Vaghasiya K, Rangaraj N, Lal J. Novel pre-clinical methodologies for pharmacokinetic drug-drug interaction studies: spotlight on “humanized” animal models. Drug Metab Rev. 2014;46:475–93.CrossRefPubMed
2.
Hasegawa M, Kawai K, Mitsui T, Taniguchi K, Monnai M, Wakui M, Ito M, Suematsu M, Peltz G, Nakamura M, Suemizu H. The reconstituted ‘humanized liver’ in TK-NOG mice is mature and functional. Biochem Biophys Res Commun. 2011;405:405–10.CrossRefPubMedPubMedCentral
3.
Yoshizato K, Tateno C. In vivo modeling of human liver for pharmacological study using humanized mouse. Expert Opin Drug Metab Toxicol. 2009;5:1435–46.CrossRefPubMed
4.
5.
Kamimura H, Ito S. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound. Xenobiotica. 2016;46:557–69.CrossRefPubMed
6.
Scheer N, Wilson ID. A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity. Drug Discov Today. 2016;21:250–63.CrossRefPubMed
7.
Nishimura T, Hu Y, Wu M, Pham E, Suemizu H, Elazar M, Liu M, Idilman R, Yurdaydin C, Angus P, Stedman C, Murphy B, Glenn J, Nakamura M, Nomura T, Chen Y, Zheng M, Fitch WL, Peltz G. Using chimeric mice with humanized livers to predict human drug metabolism and a drug–drug interaction. J Pharmacol Exp Ther. 2013;344:388–96.CrossRefPubMedPubMedCentral
8.
Yamazaki H, Suemizu H, Murayama N, Utoh M, Shibata N, Nakamura M, Guengerich FP. In vivo drug interactions of the teratogen thalidomide with midazolam: heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice. Chem Res Toxicol. 2013;26:486–9.CrossRefPubMedPubMedCentral
9.
Nagai K, Shimizu T, Togo A, Takeya M, Yokomizo Y, Sakata Y, Matsuishi T, Kato H. Decrease in serum levels of valproic acid during treatment with a new carbapenem, panipenem/betamipron. J Antimicrob Chemother. 1997;39:295–6.CrossRefPubMed
10.
De Turck BJ, Diltoer MW, Cornelis PJ, Maes V, Spapen HD, Camu F, Huyghens LP. Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin. J Antimicrob Chemother. 1998;42:563–4.CrossRefPubMed
11.
Yokogawa K, Iwashita S, Kubota A, Sasaki Y, Ishizaki J, Kawahara M, Matsushita R, Kimura K, Ichimura F, Miyamoto K. Effect of meropenem on disposition kinetics of valproate and its metabolites in rabbits. Pharm Res. 2001;18:1320–6.CrossRefPubMed
12.
Nakajima Y, Mizobuchi M, Nakamura M, Takagi H, Inagaki H, Kominami G, Koike M, Yamaguchi T. Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats. Drug Metab Dispos. 2004;32:1383–91.CrossRefPubMed
13.
Suzuki E, Yamamura N, Ogura Y, Nakai D, Kubota K, Kobayashi N, Miura S, Okazaki O. Identification of valproic acid glucuronide hydrolase as a key enzyme for the interaction of valproic acid with carbapenem antibiotics. Drug Metab Dispos. 2010;38:1538–44.CrossRefPubMed
14.
Perrier J, Durand A, Giardina T, Puigserver A. Catabolism of intracellular N-terminal acetylated proteins: involvement of acylpeptide hydrolase and acylase. Biochimie. 2005;87:673–85.CrossRefPubMed
15.
Scaloni A, Barra D, Jones WM, Manning JM. Human acylpeptide hydrolase. Studies on its thiol groups and mechanism of action. J Biol Chem. 1994;269:15076–84.PubMed
16.
Suzuki E, Nakai D, Yamamura N, Kobayashi N, Okazaki O, Izumi T. Inhibition mechanism of carbapenem antibiotics on acylpeptide hydrolase, a key enzyme in the interaction with valproic acid. Xenobiotica. 2011;41:958–63.CrossRefPubMed
17.
Suzuki E, Nakai D, Ikenaga H, Fusegawa K, Goda R, Kobayashi N, Kuga H, Izumi T. In vivo inhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs. Xenobiotica. 2016;46(2):126–31.CrossRefPubMed
18.
Gugler R, Von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet. 1980;5:67–83.CrossRefPubMed
19.
Kamimura H, Ito S, Nozawa K, Nakamura S, Chijiwa H, Nagatsuka S, Kuronuma M, Ohnishi Y, Suemizu H, Ninomiya S. Formation of the accumulative human metabolite and human-specific glutathione conjugate of diclofenac in TK-NOG chimeric mice with humanized livers. Drug Metab Dispos. 2015;43:309–16.CrossRefPubMed
20.
Miyaguchi T, Suemizu H, Shimizu M, Shida S, Nishiyama S, Takano R, Murayama N, Yamazaki H. Human urine and plasma concentrations of bisphenol A extrapolated from pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and semi-physiological pharmacokinetic modeling. Regul Toxicol Pharmacol. 2015;72:71–6.CrossRefPubMed
21.
Yamamura N, Imura K, Naganuma H, Nishimura K. Panipenem, a carbapenem antibiotic, enhances the glucuronidation of intravenously administered valproic acid in rats. Drug Metab Dispos. 1999;27:724–30.PubMed
22.
23.
Yamamura N, Imura-Miyoshi K, Naganuma H. Panipenum, a carbapenem antibiotic, increases the level of hepatic UDP-glucuronic acid in rats. Drug Metab Dispos. 2000;28:1484–6.PubMed
24.
Soars MG, Riley RJ, Findlay KA, Coffey MJ, Burchell B. Evidence for significant differences in microsomal drug glucuronidation by canine and human liver and kidney. Drug Metab Dispos. 2001;29:121–6.PubMed
25.
Sumita Y, Nouda H, Tada E, Kohzuki T, Kato M, Okuda T, Fukasawa M. Pharmacokinetics of meropenem, a new carbapenem antibiotic, parenterally administrated to laboratory animals. Jpn J Chemother. 1992;40(Suppl 1):123–31.
26.
Mitta M, Ohnogi H, Mizutani S, Sakiyama F, Kato I, Tsunasawa S. The nucleotide sequence of human acylamino acid-releasing enzyme. DNA Res. 1996;3:31–5.CrossRefPubMed
27.
Lunde JL, Nelson RE, Storandt HF. Acute seizures in a patient receiving divalproex sodium after starting ertapenem therapy. Pharmacotherapy. 2007;27:1202–5.CrossRefPubMed
28.
Haroutiunian S, Ratz Y, Rabinovich B, Adam M, Hoffman A. Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study. J Clin Pharmacol. 2009;49:1363–9.CrossRefPubMed
29.
Taha FA, Hammond DN, Sheth RD. Seizures from valproate–carbapenem interaction. Pediatr Neurol. 2013;49:279–81.CrossRefPubMed
Metadata
Title
Observation of Clinically Relevant Drug Interaction in Chimeric Mice with Humanized Livers: The Case of Valproic Acid and Carbapenem Antibiotics
Authors
Eiko Suzuki
Kumiko Koyama
Daisuke Nakai
Ryoya Goda
Hiroshi Kuga
Kan Chiba
Publication date
01-12-2017
Publisher
Springer International Publishing
Published in
European Journal of Drug Metabolism and Pharmacokinetics / Issue 6/2017
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI
https://doi.org/10.1007/s13318-017-0413-2

Other articles of this Issue 6/2017

European Journal of Drug Metabolism and Pharmacokinetics 6/2017 Go to the issue

Review Article

Preclinical Pharmacokinetics and Pharmacodynamics of Pinometostat (EPZ-5676), a First-in-Class, Small Molecule S-Adenosyl Methionine Competitive Inhibitor of DOT1L

Original Research Article

Catechol-O-Methyltransferase and UDP-Glucuronosyltransferases in the Metabolism of Baicalein in Different Species

Original Research Article

Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis

Original Research Article

Evaluating the Feasibility of Use of a Foreign Reference Product for Generic Drug Applications: A Retrospective Pilot Study

ACKNOWLEDGEMENT TO REFEREES

Acknowledgement to Referees

Original Research Article

Physiologically Based Pharmacokinetic Modelling and Prediction of Metformin Pharmacokinetics in Renal/Hepatic-Impaired Young Adults and Elderly Populations