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04 February 2015 : Clinical Research  

Serum Alanine Transaminase Total Bilirubin Concentrations Predict CYP3A Activity as Measured by Midazolam and 1’-Hydroxylation

Rui HeB, Yuhong LiAG, Jinguang RuanE

DOI: 10.12659/MSM.892044

Med Sci Monit 2015; 21:396-402

Abstract

BACKGROUND: Microsomal enzyme P450 (CYP450) plays an important role in metabolism of most xenobiotics. The activity of CYP3A decreases in patients with liver dysfunction. However, whether serum concentrations of liver enzymes reflect the activity of CYP3A is unclear. We aimed to search for a new clue to predict the activity of CYP3A and guide clinical medication.

MATERIAL AND METHODS: Forty-five patients undergoing surgery under general anesthesia were enrolled in the study, including 15 cases with normal liver function (Group N), 15 cases with moderate fatty liver according to both the results of ultrasonic diagnosis of moderate fatty liver and the laboratory results of elevated alanine transaminase less than 3 times the normal (Group M), and 15 cases with end-stage liver disease (Group S). Each patient received a single dose of 5 mg midazolam intravenously. CYP3A activity was measured by plasma 1’hydroxymidsazolam/midazolam (1’-OH-MDZ/MDZ) ratio at 2 h after administration of midazolam.

RESULTS: They was no significant difference in CYP3A activity between the patients with normal liver function and moderate fatty liver (P=0.332). The activity of CYP3A in Group S was lower than in Group N and Group M (P=0.000). Multiple linear regression analysis showed a statistically significant linear relationship between the activity of CYP3A and alanine transaminase (ALT, R2=0.682, P=0.000), and total bilirubin (TB, R2=0.519, P=0.002). There were no other factors, including albumin (ALB, P=0.881) and alkaline phosphatase (ALP, P=0.497), correlated with the activity of CYP3A.

CONCLUSIONS: We conclude that the activity of CYP3A in patients with end-stage liver disease decreased. The decrease in the activity of CYP3A was determined by the increase in the serum concentration of ALT and TB and not by patient’s age or body weight. ALT and TB therefore might have predictive value for the activity of CYP3A. An abnormal liver function test likely gives the clinician a hint about dosage adjustment.

Keywords: Alanine Transaminase - blood, Analysis of Variance, Bilirubin - blood, Biological Markers - blood, Cytochrome P-450 CYP3A - metabolism, End Stage Liver Disease - metabolism, Fatty Liver - metabolism, Hydroxylation, Linear Models, Midazolam - metabolism

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750