Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently.

Duthaler, Urs; Bachmann, Fabio; Suenderhauf, Claudia; Grandinetti, Tanja; Pfefferkorn, Florian; Haschke, Manuel; Hruz, Petr; Bouitbir, Jamal; Krähenbühl, Stephan (2022). Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently. Clinical pharmacokinetics, 61(7), pp. 1039-1055. Springer 10.1007/s40262-022-01119-0

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BACKGROUND

Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking.

OBJECTIVE

In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach.

METHODS

We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12).

RESULTS

While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration-time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1'-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged.

CONCLUSIONS

Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis.

CLINICAL TRIAL REGISTRATION

NCT03337945.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine

UniBE Contributor:

Haschke, Manuel Martin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1179-1926

Publisher:

Springer

Language:

English

Submitter:

Pubmed Import

Date Deposited:

17 May 2022 15:24

Last Modified:

17 Jul 2022 00:14

Publisher DOI:

10.1007/s40262-022-01119-0

PubMed ID:

35570253

BORIS DOI:

10.48350/170082

URI:

https://boris.unibe.ch/id/eprint/170082

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