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

Abstract

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.

Fig. 1

Pharmacokinetics of substrates with a low to moderate hepatic extraction. Plasma concentration–time profiles were assessed in n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis, and in 12 matched control subjects. The insert displays the semi-logarithmical presentation of the data. The calculated pharmacokinetic variables are displayed in Table 2. Data are presented as mean ± standard error of the mean

Fig. 2

Pharmacokinetics of substrates with a moderate to high hepatic extraction. Plasma concentration–time profiles were assessed in n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis, and in 12 matched control subjects. The insert displays the semi-logarithmical presentation of the data. The calculated pharmacokinetic variables are displayed in Table 4. Data are presented as mean ± standard error of the mean

Fig. 3

Linear correlation of the prothrombin ratio with the terminal elimination rate constant (k_e) for the substrates used in the Basel phenotyping cocktail. The population studied included n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis, and in 12 matched control subjects. k_e terminal elimination rate constant

Fig. 4

Linear correlation of the prothrombin ratio with the metabolic ratio for the substrates used in the Basel phenotyping cocktail. The population studied included n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis, and in 12 matched control subjects. The metabolic ratio was calculated as the ratio of area under the plasma concentration–time curve from 0 to 24 h for the specific metabolite and area under the plasma concentration–time curve from 0 to 24 h for the parent drug

Fig. 5

Effect of liver cirrhosis on cytochrome P450 enzyme (CYP) activity. The population studied included n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis, and in 12 matched control subjects. Cytochrome P450 enzyme activity was estimated based on the elimination rate constant (k_e) or on the metabolic ratio (MR_0–24h) of the substrates used in the Basel phenotyping cocktail. The substrates included caffeine (CYP1A2), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A). The MR was calculated as the ratio of area under the plasma concentration–time curve from 0 to 24 h for the specific metabolite and area under the plasma concentration–time curve from 0 to 24 h for the parent drug. Data are displayed as individual values and mean ± standard error of the mean. k_e terminal elimination rate constant, *p < 0.05 between patients with liver cirrhosis according to Child class vs control subjects