Effects Of Liver Function On Midazolam Concentration, Bispetral Index On Loss Of Consciousness And CYP3A Activity

Midazolam (MDZ) is a benzodiazepine with a rapid onset and short duration of action, MDZ is commonly used in clinical practice to induce anesthesia and induce sedation in patients in intensive care units. Midazolam is mainly metabolized by CYP3A4.The enzymes P450 encoded by the CYP3A gene subfamily are the most abundant forms of the total cytochrome P450 presenting in the adult human liver and small bowel. Midazolam was metabolized to its major metabolite, 1'hydroxymidazolam (1'-OH-MDZ). Its biotransformation has also been proposed as a probe for CYP3A activity in vivo. Many factors such as age, sex, and hepatic function may influence the activity of CYP3A isoforms. However, which liver function indices play the key effect on the activity of CYP3A4 remains unclear.The bispectral index (BIS) is a processed electroencephalographic parameter that has been reported possibly to be related to the hypnotic component of the anesthetic state. Therefore, BIS is widely used to quantify the hypnotic effects of anesthetics and can serve as a tool to monitor and titrate the pharmacodynamic effects of anesthetics. BIS was able to classify the degree of hepatic encephalopathy throughout its entire spectrum. Patients with obstructive jaundice have an increased sensitivity to isoflurane. The concrete influence of liver function on sensitivity to midazolam and prediction of BIS for loss of consciousness (LOC) remains unclear.The major focus of the present study was to examine the effects of liver function on midazolam concentration, bispectral index on loss of consciousness, and the activity of CYP3A4.Section one:Effects of liver function on midazolam concentration and bispetral at the time to loss of consciousnessTo investigate the effects of liver function on sensitivity to midazolam (MDZ) and prediction of bispetral index (BIS) for loss of consciousness (LOC), MDZ concentration and BIS were examined in patients with different liver function at the time to LOC. Forty-five patients underwent operation under general anesthesia were enrolled in the study including 15 cases with normal liver function (group A).15 cases with moderate fatty liver (group B) and 15 cases with end-stage liver disease (group C). Midazolam was administered using a target-controlled infusion device to increase concentration gradually. At the time to LOC, the BIS was recorded and the blood sample was withdrawn for measurement of midazolam concentration. Logistic regression analysis was used to calculate EC50 of midazolam and BIS50 at the time to LOC. The results showed that the EC50 of midazolam was 310.4 and 294.8 ng/ml (P>0.05), BIS50 were 51 and 52 in Group A and B at the time to LOC. LOC occurred at the lower EC50 of midazolam and at a high BIS50 in group C compared with groups A and B (P<0.01). The results suggest that patients with end-stage Liver disease are more sensitive to midazolam and the prediction of BIS for LOC was affected, while there are no changes in patients with minor abnormal liver function.Section two:Effects of liver function on the activity of CYP3A4The aim of this study was to investigate the effects of liver function on the activity of CYP3A4, which are the most important liver function indices involved. The patients and the experimental protocols were the same as in the section one. Each patient was administered single dose of 5mg midazolam intravenously. CYP3A activity was measured by plasma 1'hydroxymidsazolam/midazolam (1'-OH-MDZ/MDZ) ratio at 2 h after administration of midazolam. The results showed that there are significant differences of CYP3A activity in patients with different liver function (P<0.05). The activity of CYP3A in Group C was lower than in Group B, and the CYP3A activity in Group A is the highest. The result showed a statistically significant linear relationship between the activity of CYP3A and ALT (P=0.008), and between TB (P=0.005). Multiple regression analysis confirmed that no other factors, including ALB (P=0.665) and ALP (P=0.07), correlated with the activity of CYP3A. There was no correlation between body weight, age and the activity of CYP3A4 (P=0.111 and 0.244). We concluded that the activity of CYP3A4 in patients with end-stage liver disease decreased. ALT and TB were the most important key factors among all of liver function indices.