Patients' responses to drugs are often variable and sometimes unpredictable. Inconsistency in medication response can depend on the variability in the activity of drug-metabolizing enzymes . One of the most important systems of drug-metabolizing enzymes in humans is the liver cytochrome P450 enzyme family, which is responsible for the oxidative metabolism of numerous endogenous compounds and xenobiotics [2,3].
It is known that one of the major factors affecting drug-metabolizing enzyme systems is oxidative stress, which can be defined as an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants . In this case reactive oxygen species interacting with biological membrane polyunsaturated fatty acids leads to their peroxidation . Activation of lipid peroxidation (LPO) can be accompanied by pronounced structural failures of the hepatocyte endoplasmic reticulum membranes and decreasing activity of cytochrome P450-dependent monooxygenases of the liver (monooxygenase function) [5,6]. The consequences of reduction in liver microsomal oxidation can be delayed metabolism of xenobiotic and endogenous toxins, drug accumulation and endogenous toxaemia [7,8]. Evidence of marked oxidative stress is well established in patients with coronary heart disease (CHD) after cardiosurgical intervention [9,10]. In this case cardiopulmonary bypass (CPB) and tissue ischaemia–reperfusion injury play a dominant role in activation of lipid peroxidation [11–13]. It is important to note that increased levels of reactive oxygen species and reduction of antioxidant levels are related to disease severity . In patients with multiple organ dysfunction (MOD) several pathological processes (global and local hypoperfusion, hypoxia, endothelial injury, acidosis) have been related to the synthesis and discharge of large amounts of reactive oxygen species in a nonregulated mode [15–17]. We suggest that massive oxidative stress in CHD critically ill patients after cardiac surgery can damage liver cytochrome P450 enzymes, delay clearance of drugs and change the response to medications by altering blood drug concentrations. For this reason we conducted a study of oxidative stress and monooxygenase function of the liver (MFL) in patients with CHD and multiple organ dysfunction after myocardial revascularization.
Patients and methods
Local ethics committee approval and written informed consent were obtained. Twenty-seven patients with CHD aged 55.1 ± 10.1 (NYHA functional class 3.0 ± 0.6) were studied in the main group. All patients underwent aorto/mammary coronary bypass under general anaesthesia and CPB. In seven of them myocardial revascularization was combined with left ventricle postinfarction aneurysm plasty, in five with aortic valve replacement, in six with mitral valve replacement or its plasty and in three with tricuspid valve plasty. CPB was used for 162.2 ± 67 min, whereas aortic occlusion lasted for 104.7 ± 46.7 min. Postoperatively at various stages of the study all patients in the group showed more or less pronounced signs of multiple organ dysfunction. Thirty-eight patients with CHD with uncomplicated follow-up (NYHA functional class 2.9 ± 0.5) were included in the control group. All patients from this group underwent myocardial revascularization under general anaesthesia and CPB. Aortic/mammary coronary bypass combined with aneurysmoplasty was used in five patients, three received aortic valve replacement, the mitral valve was either replaced or repaired in two patients, and two patients underwent tricuspid valve plasty. CPB and aortic occlusion lasted for 156.3 ± 60 and 98.2 ± 41.8 min respectively. The patients in both groups were comparable with respect to medical history, general anaesthesia, ventilation management, bypass and crossclamp time. Neither chronic hepatitis nor alcoholic overconsumption was observed in patients of either group. Neither prolonged hypotension nor other severe events were observed during surgery in all patients.
Multiple organ dysfunction diagnosis and evaluation was carried out with the SOFA (Sequential Organ Failure Assessment) system . The MOD parameters for six possible organ dysfunctions (cardiovascular, neurological, respiratory, renal, hepatic, coagulation) and the total score for each patient during the postoperative period were taken into account. The most abnormal value for each clinical and laboratory parameter included in the SOFA system was recorded daily and then transformed into the dysfunction score, graded from 0 to 4. The SOFA score was calculated by summing the worst scores for each of the six organ systems on the day of assessment.
The LPO intensity was investigated by analysing malon dialdehyde  and conjugated trienes , which are secondary products of polyunsaturated fatty acid peroxidation and are used to monitor lipid oxidation in biological systems. Antioxidant lipid protection (ALP) intensity was evaluluated by the hepatocuprein  and catalase levels in plasma . Hepatocuprein is an enzyme which oxidizes and connects ions of iron without formation of free radicals and is used to monitor the antiradical component of the ALP system . Catalase is an endocellular antioxidant which decomposes hydrogen peroxide with allocation of oxygen and is used to monitor the antiperoxidation link of the ALP system .
The MFL status was assessed by pharmacokinetic parameters of antipyrine. Biotransformation of antipyrine occurs in two phases (oxidation and conjugation) and generally reflects the metabolism of the majority of lipophilic chemical compounds. As it has only an insignificant speed of metabolism, antipyrine has a hepatic clearance which depends on liver blood flow to only a small degree. Antipyrine metabolism is a measure of the integrated activity of liver microsomal monooxygenases. Pharmacokinetic data of antipyrine are often used to study the effects of other drugs or diseases on liver monooxygenase function [23,24]. All patients received antipyrine (10 mg kg−1 of body weight) at 9 o'clock in the morning. In order to analyse antipyrine concentrations, blood or saliva samples were collected 3, 6, 9, 12 and 24 h after antipyrine administration. Concentrations of antipyrine in plasma or saliva were determined by spectrophotometry , while measuring its half-life (T½ AP), clearance (Cl AP) and distribution volume (Vd AP). It should be noted that an increase in both antipyrine half-life and reduction in its clearance indicates a decrease in MFL. The intensity of oxidative stress and MFL, as well as MOD severity index (according to the SOFA scale), were evaluated on admission and on the first, third to fourth and 10th to 12th postoperative days. Normal data of oxidative stress and MFL from our laboratory were also used in this study.
All data were tested for normal distribution using the Kolomogorov–Smirnov test. Normally distributed data are expressed as means ± SD. Differences between groups were analysed using the t-test for independent samples, Dunnett's method for multiple comparisons as well as Pearson's correlation coefficient. P < 0.05 was considered to be statistically significant.
Preoperative examination revealed no MOD symptoms in patients in either group. In the course of studying oxidative stress in both groups an elevated level of LPO metabolites as compared with normal parameters was observed. The concentration of plasma conjugated trienes in both groups was equal to 0.98 ± 0.47 and 0.99 ± 0.39 units of optical density. Malon dialdehyde (MDA) levels were 6.52 ± 1.19 and 6.48 ± 1.36 nmol l−1. The levels of hepatocuprein and catalase did not differ essentially from normal. Although studying MFL, it was found that the T½ of antipyrine in both the main and control groups increased up to 14.4 ± 4.4 and 18.5 ± 18.0 hours, whereas there was no significant difference in Cl antipyrine values as compared with normal parameters in both groups (see Table 1).
During the first day after operation the total MOD severity index (according to the SOFA scale) in patients in the main group considerably increased up to 6.85 ± 0.94 points. Although investigating the prevalence and severity of different systems failures, it was found that abnormalities in cardiovascular and pulmonary function amounted to 30.7% and 23.3%, coagulation and creatinine changes were 18.0% and 17.7%, bilirubin alteration and neurological disorder accounted for 6.4% and 3.9% (see Table 2). Over the same period the level of conjugated trienes in both groups increased by 84.7% and 63.6%. MDA concentration in the main group increased by 16.3%, whereas that in the control group remained the same as baseline. The content of hepatocuprein in both groups decreased by 28.3% and 21.4%. The activity of catalase increased by 28.2% and 70.1%. At this stage T ½ antipyrine in the main group increased by 70.1%, whereas Cl antipyrine decreased by 38%. In the control group T ½ antipyrine did not change significantly, while Cl antipyrine dropped by 24% compared with the preoperative data (see Tables 3 and 4).
During the third to fourth day after operation the total MOD severity index in the main group decreased to 2.64 ± 0.66 points. The structural analysis of organ failures showed that the abnormalities in coagulation and cardiovascular system amounted to 34.6% and 30.3%, those of creatinine and respiratory changes made up 25.4% and 3.5%, whereas the bilirubin change and neurological disorders was equal to 3.0% and 3.0% (see Table 2). Over the same period the conjugated triene values in both groups decreased, although remaining increased by 69.4% and 32.3% as compared with the baseline. The content of MDA increased while exceeding the preoperative level by 37.7% and 14.2%; hepatocuprein concentration increased to the preoperative values. The activity of catalase in the main group increased insignificantly, that in the control group decreased while exceeding the baseline by 35.1% and 43.9%. At this stage the numbers of antipyrine pharmacokinetic parameters in the main group did not differ significantly from the baseline, whereas in the control group T ½ antipyrine decreased by 50.3% and Cl antipyrine increased by 46% compared with the preoperative values (see Tables 3 and 4).
During the 10th to 12th day after operation the total MOD severity index in patients in the main group equalled 2.79 ± 0.67 points. At this stage creatinine change and cardiovascular abnormality accounted for 40.9% and 19.7%, neurological and pulmonary disorders 15.0% and 13.3%, and bilirubin and coagulation changes made up 7.2% and 3.9% (see Table 2). On the 10th to 12th day after operation a further reduction in conjugated trienes as well as an increase in MDA and hepatocuprein was observed in patients in both groups. Thus, the content of conjugated trienes in the main group exceeded the preoperative value by 34.7%, with the value in the control group being equal to the baseline. MDA concentration in the main and control groups increased by 41.3% and 22.8%. The level of hepatocuprein in the main group reached baseline, whereas that in the control group exceeded baseline by 16.7%. The activity of catalase in both groups substantially decreased. In the main group the catalase level was close to the preoperative value, whereas in the control group it exceeded the baseline by 36.8%. At the same time T ½ antipyrine in the main group increased by 54.2% and Cl antipyrine decreased by 35.6% compared with the baseline. Conversely, in the control group the MFL parameters matched the preoperative values (see Tables 3 and 4).
When comparing PLO and ALP parameters, depending on the nature of the postoperative period, it was found that, on the first, third to fourth and 10th to 12th days after myocardial revascularization, the intensity of lipid peroxidation processes and the rate of lowering the antiradical component of the ALP system were more pronounced in patients of the main group than in the control one. Conversely, over the same periods the antiperoxidation link of the ALP system increased more rapidly in patients in the control group than in the main one. Similarly, when comparing MFL parameters it was found that more pronounced slowdown of hepatic metabolism during the first postoperative day was typical in the main group compared with the control one. Moreover, from then on, the dynamics of hepatic metabolism in the control group was just the reverse of that in the main group. If on the third to fourth and 10th to 12th day after operation MFL in the main group tended to slow down or considerably decreased, the speed of monooxygenase reactions in the liver in the control group would increase considerably or match the baseline.
Studying the correlation dependence between the parameters of multiple organ dysfunction and the intensity of oxidative stress during the first postoperative day showed an inverse relationship between the total MOD severity index and the hepatocuprein level (r = −0.46; P < 0.05), as well as a direct dependence of the number of organ failures on MDA concentration (r = 0.34; P < 0.05). Investigating the dependence between the parameters of multiple organ dysfunction and hepatic metabolism on the 10th to 12th day after operation demonstrated a negative relationship between the number of organ failures and Cl antipyrine values (r = −0.53; P < 0.05). When carrying out a correlation analysis of MFL and LPO–ALP parameters in the main group, it was found that there was a direct dependence of T ½ antipyrine on the MDA level on the first and 10th to 12th day after operation (r = 0.31; r = 0.43; P < 0.05), an inverse dependence of Cl antipyrine on MDA and catalase parameters during the 10th to 12th day after operation (r = −0.48; r = −0.46; P < 0.05), as well as a direct dependence of Cl antipyrine on catalase activity on the third to fourth day after operation (r = 0.65; P < 0.05).
Before operation moderate activation of lipid peroxidation and insignificant slowdown of hepatic metabolism against a background of absence of clinical/laboratory signs of MOD in patients with both complicated and uncomplicated follow-up were observed.
On the first postoperative day apparent signs of MOD were observed in patients in the main group, with all parameters under study being increased. The most significant changes were seen in the cardiovascular, respiratory and renal systems. Over the same period a substantial increase in LPO intensity and antiperoxidation link of the ALP system was found, with its antiradical component depressed in both groups. Examining MFL revealed that marked slowdown of microsomal oxidation in the liver was typical of the main group, whereas there was only a slight impairment in hepatic metabolism as compared with the baseline in the control group.
On the third to fourth day after operation the severity of MOD syndrome in the main group considerably decreased. The most significant and frequent failures were seen in coagulation, as well as in the cardiovascular and renal systems. Over the same period the intensity of LPO and antiperoxidation link of the ALP system remained elevated in both groups, with the activity of its antiradical link increasing. Examining antipyrine pharmacokinetics revealed that the level of hepatic metabolism in the main group considerably increased as compared with that at the previous stage and did not differ significantly from the baseline. The MFL in the control group was not only equal to its rate at the preoperative stage but it was appreciably higher.
On the 10th to 12th day after operation the severity of MOD in the main group remained practically the same and was in line with that observed over the previous period. The most frequent and pronounced failures were seen in the cardiovascular and renal systems. Over the same period the intensity of LPO and antiperoxidation link of the ALP system in both groups markedly decreased and the activity of its antiradical link increased further. Examining MFL revealed that the activity of liver microsomal enzymes in the main group considerably decreased and was lower by one and half times the value at baseline. The hepatic metabolism level in the control group remained high and matched the preoperative values.
When comparing oxidative stress and MFL parameters, depending on the nature of the postoperative period, it was found that MOD was accompanied on the one hand by more marked activation of LPO processes and depression of the ALP system and on the other hand by a more pronounced reduction in MFL than in an uncomplicated postoperative period. The data obtained could be attributed to global hypoperfusion and hypoxia typical of multiple organ dysfunction, as well as to an increase in the number of free radicals capable of depressing the activity of P450 dependent monooxygenase cytochromes in the liver. In this respect, the correlation analysis results are of some interest. The relationships between MOD parameters and intensity of oxidative stress/hepatic metabolism bear witness to both a potentiating impact of multiple organ dysfunction on LPO processes and a damaging action of MOD on the microsomal monooxygenase system of the liver. On the contrary, relationships between MFL and LPO–ALP parameters demonstrate both a depressive effect of lipid peroxidation on hepatic metabolism and a protective role of the antioxidant system for the microsomal enzymes of hepatocytes.
It is obvious that the set of factors specifying the decrease in MFL is of a more complex nature and includes, along with oxidative stress, acute inflammatory response, endotoxaemia and sepsis [7,26,27]. This conclusion is confirmed by the dynamics of oxidative stress/MFL parameters in patients with MOD, when on the one hand the intensity of LPO decreased and ALP recovered, whereas on the other hand hepatic metabolism substantially slowed down. Presumably, a significant role in reducing the activity of liver microsomal monooxygenases is associated with a systemic inflammatory response syndrome and, specifically, its aggressive proinflammatory transmitters, the synthesis of which substantially increases after myocardial revascularization and under multiple organ dysfunction [7,28,29]. The current results of the studies have shown that circulating plasma concentrations of proinflammatory cytokines (e.g. tumour necrosis factor-α and interleukin-6) are elevated in patients with heart failure and these cytokines downregulate cytochrome P450 enzyme activity . Recently, it was shown that production of interleukin-6 and nitric oxide is elevated in children with sepsis-induced multiple-organ dysfunction. In this population cytochrome P450-mediated drug metabolism is decreased, related in part to the degree of inflammation and organ failure . It has been shown that the overproduction of nitric oxide observed in an animal model is partially responsible for the substantial decrease in the liver drug-metabolizing enzyme activity that may take place in a Gram-negative bacterial infection . In addition to cytokines and nitric oxide, glucocorticoids may have an important role in cytochrome P450 regulation under stress conditions, including that caused by the inflammatory stimulus. Glucocorticoids exert bimodal effects on cytochrome P450 expression in hepatocytes: induction at low concentrations, and suppression at high concentrations .
It is generally accepted that liver cytochrome P450 enzymes are the most important system in humans, as it is responsible for the metabolism of many drugs [2,3]. In numerous studies it has been shown that midazolam, barbiturates, propofol, vecuronium, propranolol, nifedipine, organic nitrate, angiotensin-converting enzyme inhibitors and warfarin are almost exclusively metabolized by hepatic cytochrome P450 enzyme systems [31–36]. In clinical practice several examples have been reported indicating compromised drug clearance and changes in pharmacokinetics during diseases with an inflammatory factor or during infections [7,34,36]. Some studies suggest that for any drug that is metabolized by MFL and that has a narrow therapeutic index, there is a significant risk in placing patients in a position where inflammation and infection might lead to aberrant drug handling and an adverse drug response [27,35]. It has been shown that an endotoxin-induced decline in cytochrome P450-mediated enzyme activity from Gram-negative bacterial infection may augment the risk of the side effects of some drugs, which are metabolized by the liver . Recently evidence was provided that in children with sepsis and organ failure for drugs metabolized by cytochrome P450 enzymes there is an urgent need to re-evaluate the use of standard drug dosage schedules in the sepsis population . Frye and colleagues  reported that cytokine-mediated decreases in drug metabolism might contribute to observed variability in drug response and enhance the risk of adverse drug effects in heart failure patients.
Despite existing results, the information on liver cytochrome P450 enzyme activity and how drugs behave in cardiac critically ill patients is missing. In this study we were able to demonstrate that CHD patients with MOD have a significant decrease in liver monooxygenase function. Our results showed a considerable role of oxidative stress in suppression of liver microsomal monooxygenase activity. For evaluation of liver cytochrome P450 enzyme activity we used the pharmacokinetic parameters of antipyrine. It is already known that antipyrine metabolism, reflecting the whole activity of liver cytochrome P450 enzymes, is considered a ‘gold standard’ measure of mixed cytochrome P450-mediated drug metabolism in humans [23,24]. The antipyrine test is reliable, inexpensive and can find clinical application in monitoring of liver drug-metabolizing enzyme capacity in critically ill patients. The decline of antipyrine elimination testifies to MFL depression, which can lead to delay of metabolism of drugs with their accumulation and alteration in pharmacology [7,26]. In our previous study  we demonstrated that reduction in MFL after surgical correction of hypercorticism in refractory arterial hypertension patients led to a significant decrease in tolerance to hypotensive drugs, including nifedipine, propranolol and enalapril, which required reduction in their dosage and administration frequency. Undoubtedly, the data obtained on slowdown of microsomal oxidation in the liver point to the necessity of a more accurate adjustment of standard doses of pharmaceuticals while treating CHD patients with MOD in the early postoperative period.
In conclusion, this is first study evaluating liver cytochrome P450 enzymes in CHD patients with MOD after cardiac surgery; however, our data have demonstrated that patients with multiple organ dysfunction have considerably more oxidative stress and decrease in liver monooxygenase function (one and a half times) than in those with an uneventful postoperative period after myocardial revascularization. Activation of lipid peroxidation is one of the main reasons for suppression of microsomal monooxygenase activity of the liver in CHD patients with multiple organ dysfunction in the early postoperative period. Slowdown of liver microsomal oxidation processes might change pharmacokinetic response of coronary heart disease patients undergoing drug therapy and therefore requires a more careful approach to its administration.
The study was funded by Academician E. Meshalkin Research Institute of Circulation Pathology, Novosibirsk, Russia. The results were presented in part at the Congress of the World Society of Cardio-Thoracic Surgeons, Kyoto, Japan, 2007.
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