Drug Metabolizing Capacity Of The Liver In Liver Donors Recovers Fully By One Month Post Donation

M. Miah¹, X. Wu¹, I. H. Shaik¹, H. J. Johnson¹, S. Ganesh², M. Molinari², A. D. Tevar², C. Hughes², A. Humar², R. Venkataramanan¹

¹Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, ²Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA

Meeting: 2019 American Transplant Congress

Abstract number: B356

Keywords: Donation, Liver metabolism, Pharmacokinetics

Session Information

Session Name: Poster Session B: Liver: Living Donors and Partial Grafts

Session Type: Poster Session

Date: Sunday, June 2, 2019

Session Time: 6:00pm-7:00pm

Presentation Time: 6:00pm-7:00pm

Location: Hall C & D

*Purpose: In liver donors, hepatic volume recovers to pre donation values in 2-6 months after surgery. However, there is limited information on the recovery of hepatic/metabolic activity during the hepatic regeneration phase. We evaluated the activity of Phase I and Phase II drug metabolizing enzymes in liver donors, using probe substrates pre, and up to 6 months post liver donation.

*Methods: Liver donors received acetaminophen, caffeine, and dextromethorphan orally and provided saliva and cumulative urine samples for 24h, before liver donation, and 1 week, 1, 3 and 6 months after donation. Saliva and urine samples were analyzed for acetaminophen (A) and its glucuronide (AG) and sulfate (AS) metabolites; caffeine, its metabolites paraxanthine and 1,7-dimethyluric acid; dextromethorphan, its O-demethylation and N-demethylation metabolites using an UPLC-MS/MS assay. Based on these, glucuronidation, sulfation, CYP1A2, CYP2A6, CYP2D6 and CYP3A4, activities were estimated at different times. The activity of each enzyme post donation was compared to respective activity pre donation. The groups were compared using Mann-Whitney test and a p<0.05 was considered statistically significant.

*Results: The activities of CYP1A2, CYP2D6 and CYP3A4 at one week post-surgery were not significantly reduced compared to pre surgery values, while CYP2A6 activity estimated as ratio of 1,7-dimethyluric acid to paraxanthine in urine showed a significant decrease from 1.9±0.7 at pre surgery to 0.7±0.4 at 1 week post donation, but recovered fully by 1 month (1.2±0.4). Glucuronidation measured as ratio of AG/A and sulfation estimated as ratio of AS/A were significantly lower by 40% (24.2±11.7 vs 14.1±10.6) and 60% (13.2±4.5 vs 5.2±3.5) respectively at 1 week after donation, but recovered to normal by 1 month post-surgery [AG/A (26.0±8.3); AS/A (11.0±1.1].

*Conclusions: Despite significant reduction in liver size immediately after partial liver resection, the activity of several CYP enzymes was minimally affected 1 week after surgery. All the hepatic drug metabolizing activities tested appear to return to normal (pre-surgery values) by 1 month after donation.

To cite this abstract in AMA style:

Miah M, Wu X, Shaik IH, Johnson HJ, Ganesh S, Molinari M, Tevar AD, Hughes C, Humar A, Venkataramanan R. Drug Metabolizing Capacity Of The Liver In Liver Donors Recovers Fully By One Month Post Donation [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/drug-metabolizing-capacity-of-the-liver-in-liver-donors-recovers-fully-by-one-month-post-donation/. Accessed November 22, 2024.

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