ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO2364

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

Session Information

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

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

Authors

  • Rattanacheeworn, Punyabhorn, Chulalongkorn University Faculty of Medicine, Bangkok, Thailand
  • Kittanamongkolchai, Wonngarm, Chulalongkorn University Faculty of Medicine, Bangkok, Thailand
  • Townamchai, Natavudh, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • Udomkarnjananun, Suwasin, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • Praditpornsilpa, Kearkiat, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • Kerr, Stephen J., Biostatistics Excellence Center, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • Thanusuwannasak, Thanundorn, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand
  • Udomnilobol, Udomsak, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand
  • Jainmongkol, Suree, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand
  • Ongpipattanakul, Boonsri, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand
  • Prueksaritanont, Thomayant, Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand
  • Avihingsanon, Yingyos, Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • Chariyavilaskul, Pajaree, Chulalongkorn University Faculty of Medicine, Bangkok, Thailand

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. AUC0-last and maximum plasma drug concentration (Cmax) were increased in Gr2 and 3 compared to those in Gr1 (AUC0-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; Cmax: 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). AUC0-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). Cmax 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.