Kidney Week

Abstract: PO2364

CYP3A and Drug Transporter Activity Changes in Thai Elderly with CKD Assessed Using a Microdose Cocktail

Session Information

• Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Rattanacheeworn, Punyabhorn, Chulalongkorn University Faculty of Medicine, Bangkok, Thailand

Punyabhorn Rattanacheeworn,

• Kittanamongkolchai, Wonngarm, Chulalongkorn University Faculty of Medicine, Bangkok, Thailand

Wonngarm Kittanamongkolchai,

• Townamchai, Natavudh, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Natavudh Townamchai,

• Udomkarnjananun, Suwasin, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Suwasin Udomkarnjananun,

• Praditpornsilpa, Kearkiat, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Kearkiat Praditpornsilpa,

• Kerr, Stephen J., Biostatistics Excellence Center, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Stephen J. Kerr,

• Thanusuwannasak, Thanundorn, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand

Thanundorn Thanusuwannasak,

• Udomnilobol, Udomsak, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand

Udomsak Udomnilobol,

• Jainmongkol, Suree, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand

Suree Jainmongkol,

• Ongpipattanakul, Boonsri, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand

Boonsri Ongpipattanakul,

• Prueksaritanont, Thomayant, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand

Thomayant Prueksaritanont,

• Avihingsanon, Yingyos, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Yingyos Avihingsanon,

• Chariyavilaskul, Pajaree, Chulalongkorn University Faculty of Medicine, Bangkok, Thailand

Pajaree Chariyavilaskul,

Group or Team Name

• Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Chulalongkorn University

Background

Chronic kidney disease (CKD) may influences cytochrome P450 (CYP) enzymes and drug transporters activity, resulting in the change of pharmacokinetics. This study investigated the effect of age and renal function on activity of CYP3A and various drug transporters in healthy Thai elderly and CKD patients using a validated microdose probe substrate cocktail.

Methods

Fifty three subjects were studied [healthy young subjects (Gr1, n=20), healthy elderly (Gr2, n=16) and elderly CKD patients (Gr3, n=17)]. Each subject was given a single dose of the microdose cocktail consisted of midazolam (M; for CYP3A), dabigatran etexilate (D; for gut P-gp), pitavastatin (P; for OATP1B), rosuvastatin (R; for BCRP, OATP, P-gp), and atorvastatin (A; for OATP, BCRP, P-gp, CYP3A). Plasma samples were collected at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours after dosing. All plasma drug concentrations were measured using a fully validated LC/MS/MS. Area under the concentration-time curve (AUC) were calculated by the trapezoidal rule.

Results

No side effect was observed. Multivariate analysis, adjusted for body mass index, co-morbidity and liver functions) showed negative effects of ageing and CKD on drug transporters activity. AUC_0-last and maximum plasma drug concentration (C_max) were increased in Gr2 and 3 compared to those in Gr1 (AUC_0-last in Gr2 and 3, respectively: M 2.19 and 2.68 folds, D 1.65 and 4.43 folds, P 0.99 and 1.57 folds, R 1.43 and 1.83 folds, and A 2.19 and 4.20 folds; C_max: M 1.83 and 1.86 folds, D 1.23 and 1.61 folds, P 1.22 and 1.90 folds, R 1.12 and 1.59 folds, and A 2.28 and 4.22 folds). AUC_0-last of Gr3 were significantly increased when compared to Gr2 in D, P and A (2.69 (p<0.001), 1.59 (p<0.001) and 1.92 (p=0.001) folds, respectively). C_max were significantly increased only in P and A (1.70 (p<0.001) and 1.94 (p<0.001) folds, respectively).

Conclusion

Independent of ageing, CKD itself further reduces the activity of drug transporters, suggesting that this information has to be taken into account when drugs that pass through those transporters are prescribed to CKD patients.

Funding

• Government Support - Non-U.S.