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. 2020 May 6;28(2):479–487. doi: 10.1007/s40199-020-00350-z

Evaluation of hepatic CYP2D1 activity and hepatic clearance in type I and type II diabetic rat models, before and after treatment with insulin and metformin

Navid Neyshaburinezhad 1, Maryam Seidabadi 1, Mohammadreza Rouini 1, Hoda Lavasani 1, Alireza Foroumadi 2, Yalda H Ardakani 1,3,✉
PMCID: PMC7704830  PMID: 32378154

Abstract

Introduction

Conversion in the metabolism of drugs occurs in diabetes mellitus. Considering the importance of metabolic enzymes’ activities on the efficacy and safety of medicines, the changes in liver enzymatic activity of CYP2D1 and its related hepatic clearance, by using Dextromethorphan as probe in the animal model of type I and type II diabetes, before and after treatment, was assessed in this study.

Methods

Male Wistar rats were randomly divided into 6 groups. Seven days after induction of diabetes type I and type II, treatment groups were received insulin and metformin daily for 14 days, respectively. In day 21, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing Dextromethorphan as CYP2D1 probe. Perfusate samples were analyzed by HPLC fluorescence method in order to evaluate any changes in CYP2D1 activity.

Results

The average metabolic ratio of dextromethorphan and hepatic clearance were changed from 0.012 ± 0.004 and 6.3 ± 0.1 in the control group to 0.006 ± 0.0008 and 5.2 ± 0.2 in the untreated type I diabetic group, and 0.008 ± 0.003 and 5.0 ± 0.6 in the untreated type II diabetic rats. Finally, the mean metabolic ratio and hepatic clearance were changed to 0.008 ± 0.001 and 5.4 ± 0.1, and 0.013 ± 0.003 and 6.1 ± 0.4 in the treated groups with insulin and metformin, respectively.

Conclusion

In type I diabetic rats, corresponding treatment could slightly improve enzyme activity, whereas the hepatic clearance and enzyme activity reached to the normal level in type II group.

Graphical abstract.

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Keywords: CYP2D1 phenoconversion, Hepatic clearance, Diabetes type I, Diabetes type II, Insulin, Metformin

Introduction

Diabetes mellitus as a chronic disorder is one of the most complicated disease that can affect the quality of almost all organs through causing damages of micro and macro vessels [1, 2] and disrupting other physiological processes like interfering with lipogenesis, protein synthesis and gluconeogenesis [3–5]. As a result of this complex situation, stricken person will have to use several medications like anti-diabetic drugs, anti-hyperlipidemia agents, anti-hypertensive medicines, etc. Administration of multiple medicines in these patients will increase the risk of adverse drugs reactions [6].

One of important factors that may lead to enhance the unwanted effects or change in the efficacy of medications, is alteration in the capacity of metabolism process in patient’s body [7]. It also has been demonstrated that some acute and chronic disease could affect the metabolism process. It is believed that these alterations mostly occur in inflammatory conditions like cancers, infectious disease, myocardial infarction, etc. [8, 9]. Diabetes is an inflammatory disease, by means of experiencing the rise of some inflammatory cytokines like TNF-α, IL-1β and IL-6 in diabetic patients [10, 11]. Thereupon, it is probable to observe metabolism conversion in these patients.

Cytochrome P450s (CYP450) family is one the most vital factors in metabolism process in humans [12]. Mostly these enzyme family can be found in liver; but there are some other organs that contain these kind of metabolizing enzymes like kidneys, small intestine, etc. [13]. According to above, it appears that the evaluation of CYP450 enzymes activities is an important issue in chronic inflammatory conditions like diabetes mellitus [14]. Providing the capacity to assess the overall state of metabolism in the patient’s body and, therefore, a better assessment of the side effects of the given medications or possibly their ineffectiveness.

One of the most important CYP450 isoenzymes in humans is CYP2D6 with a crucial enzyme activity involving in biotransformation of virtually all therapeutic classes, like antiarrhythmics, tricyclic and second-generation antidepressants, antipsychotics, β-blockers, as well as anti-cancer drugs, selective estrogen receptor modifier (SERM) tamoxifen, several opioid analgesics including codeine and tramadol, and many others [15].

In order to evaluate any possible changes in CYP2D6 activity according to diabetes and also assessing the influence of receiving the corresponding treatment, an animal model of diabetes was considered in this study. It has been demonstrated that CYP2D1 is the rat orthologue of human CYP2D6 [16, 17]. Since the streptozotocin-induced diabetes animal models was widely used in pharmacokinetic studies [18, 19], streptozotocin-induced type I and streptozotocin-nicotinamide induced type II diabetic rat models were applied in this study.

On the other hand, liver perfusion has been used extensively in pharmacological and toxicological studies in recent years [20]. In this method, the liver is discrete from other organs by preserving the structure, function, and vascular system. One of the most important advantages of this method is the relatively constant liver flow, which leads to minimal observed changes in the distribution and metabolism of various drugs due to the dependency of these processes to the liver blood flow.

Finally, in this research, the possible effects of post-treatment effects of insulin and metformin administration on CYP2D1 activity and hepatic clearance was examined in type I and type II diabetic rat perfused liver model by measuring changes in the ratio of dextrorphan (DXO) to dextromethorphan (DM) as an accepted probe for evaluating the rat CYP2D1 [21] and human CYP2D6 [22, 23].

Materials and methods

Materials and reagents

Streptozocin injectable solution, was bought from thirteen Aban Pharmacy (Tehran, Iran). Nicotinamide was purchased from Merck (Darmstadt, Germany). The insulin NPH (Lansulin N®) was purchased from Exir Pharmaceutical Co. (Tehran, Iran). Metformin was purchased from thirteen Aban Pharmacy (Tehran, Iran). DM and its two metabolites, DXO (O-demethylated dextromethorphan) and HYM (N-demethylated dextromethorphan) as an Internal Standard (IS) were obtained from medicinal chemistry department, School of Pharmacy, Tehran University of Medical Science (Tehran, Iran) and their structures confirmed by H-NMR and CNMR in our laboratory. The HPLC (high performance liquid chromatography) grade acetonitrile and methanol were from Duksan Pure Chemicals Co. Ltd. (Gyeonggi-do, Korea). Ultra-pure water was obtained from a Millipore Direct-Q™ system (Millipore` Corp., France) in our laboratory whenever it was necessary. All other analytical-grade chemicals were purchased from Merck (Darmstadt, Germany) unless otherwise stated.

Animals

Twenty-four Male Sprague–Dawley rats (weighing about 250–300 g) were provided by School of Pharmacy, Animal Laboratory (Tehran, Iran). All rats were housed under constant conditions with a 12-h day/night cycle and free access to water and rodent chow. For induction of diabetes mellitus type I, a single intraperitoneally (I.P.) dose of Streptozotocin (STZ), 65 mg/kg, freshly dissolved in 100 mM sodium citrate buffer at pH 4.5, injected to overnight fasted rats. To induce type II diabetes, after 12 h of fasting, firstly, 110 mg/kg Nicotinamide (dissolved in normal saline) was intraperitoneally injected. Then after 15 min, 65 mg/kg Streptozotocin (dissolved in citrate buffer; pH = 4.5) was intraperitoneally injected. Induction of diabetes was confirmed by fasting blood glucose level using Glucocard 01 (Arkray, Japan). As shown in several studies (1–3), there are few scientific methods to simulate the exact diabetes mellitus status in animal models. STZ and STZ + Nicotinamide induced diabetic rats were introduced as one of the accepted diabetes induction methods in this field. So, according to this model, the rats with the measured fasting blood glucose of more than 400 mg/dL and 200 mg/dL on the 7 days following STZ/ STZ + Nicotinamide administration were considered as type I and Type II diabetic rats, respectively. It should be noted that despite the scientific acceptance of these models, they do not resemble all the complex nature of T1D and T2D. Also, several studies have shown that diabetes mellitus could be defined as a chronic inflammatory condition with raising of inflammatory cytokines levels [24–27]. So, increasing the inflammatory cytokines levels due to diabetes induction could be assumed in these animal models. In addition, all treatments were postponed for one week after induction of diabetes to maximize the potential effect of diabetes on increasing levels of inflammatory cytokines and, therefore, altering the CYP2D1 activity as well as minimize the effect of STZ or STZ + Nicotinamide administration.

Study design

All rats were divided by random into 6 groups consisting of 4 rats (totally 24 rats):

  1. Control group of healthy rats.

  2. Untreated type I diabetic rats (without any treatment).

  3. Type I diabetic rats received insulin.

  4. Untreated type II diabetic rats (without any treatment).

  5. Type II diabetic rats received metformin.

  6. Control group of healthy rats received metformin

The rats treated with insulin were given 6–8 IU S.C. of isophane insulin (10 IU/mL) per day for 14 days. In metformin recipients, 200 mg/kg of metformin (dissolved in 4 ml normal saline) was orally administrated once a day for 14 days after diabetes induction. Non-diabetic normal rats (group 1) and untreated diabetic rats (group 2) only received normal saline solution. After 3 weeks of diabetes induction, isolated perfused rat liver model was applied to investigate the hepatic CYP2D1 activity. Before rat liver perfusion, Fasting Blood Glucose (FBG) of rats were measured with Glucocard 01 (Arkray, Japan).

The protocol was approved by the Ethics Committee of the Institute of Pharmaceutical Sciences (TIPS) with code number of [IR.TUMS.PSRC.REC.1396.3038].

Isolated liver perfusion study

The rats were anesthetized with injection of 4:1 mixture of ketamine 10% and xylazine 2% intraperitoneally. In order to perfusing of isolated liver, the portal vein and inferior vena cava (as input and output of the perfusion medium, respectively) were cannulated in each rat. The bile duct and superior vena cava was blocked. The perfusion medium, Krebs–Henseleit buffer containing DM (300 μM) as probe, was freshly prepared. The inferior vena cava was used as the outlet duct for sampling and the perfusate samples (1 ml) were collected immediately after wash and then every 5 min, for the first 30 min and every 10 min, for the second 30 min and stored at −70 °C until analysis after centrifugation. Liver transaminases activities (AST and ALT) were also continuously monitored by a spectrophotometric method used as a measure of liver viability as it has been described by Kebis, A. et al. [28].

Apparatus and chromatographic condition

The HPLC fluorescence method was performed according to the same method and conditions was previously described by Lin et al., [29] with a slight modification.

Pharmacokinetic parameters

The metabolic ratios at different times were calculated using metabolite concentration divided by parent drug concentration at each time point.

In order to determine mean concentration of DM and its metabolite at steady state, the average concentration of each compound in perfusate at 40, 50 and 60 min of liver perfusion was calculated.

DM hepatic clearance was calculated using the following equation:

CLml/min=E×Q.

In this equation, Q equals the perfusion flow rate, which was calculated at laboratory tests of 8.3 ml/min.

DM hepatic uptake (E) was calculated as follows:

E=1−F.

In this equation, the bioavailability (F) was calculated by the following formula:

F=Coutlet/Cinlet

In this equation, the Cinlet is the mean of three final DM concentrations of liver entry in each test and Coutlet is the mean of three final DM concentrations of liver output [30].

Statistical analysis

All data in this study were expressed as mean ± SEM. An unpaired t-test was employed in this study in order to determine differences between means of groups (p < 0.05).

Results

Effect of type I diabetes on CYP2D1 activity

The result of this research indicated that type I diabetes mellitus can significantly reduce the activity of CYP2D1; in which the mean metabolic ratios of DM was changed from 0.012 ± 0.004 in the control group to 0.006 ± 0.001 in the untreated rats (p˂ 0.05) (Fig. 1a). As it has been expected, Fasting Blood Glucose (FBG) levels of diabetic rats was significantly increased compared to control group (471 ± 32 mg/dl vs 75 ± 4 mg/dl) (p˂ 0.001) (Fig. 3a).

Fig. 1.

Fig. 1

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Perfusate mean metabolic ratio profile (3 endpoints) in all type I diabetic groups compared to control rats, following the passage of the perfusion buffer containing 300 μM dextromethorphan through the portal vein (mean ± SEM) (a). Perfusate mean metabolic ratio profile (3 endpoints) in all type II diabetic groups compared to control rats, following the passage of the perfusion buffer containing 300 μM dextromethorphan through the portal vein (mean ± SEM) (b). Each group contains 4 rats. Each experiment was repeated independently three times in triplicate tests and data are shown as mean ± SEM. *P ≤ 0.05; **P ≤ 0.01

Fig. 3.

Fig. 3

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Fasting Blood Glucose (mg/dl). FBG of control group and insulin receiving groups in comparison with untreated type I diabetic rats (a). FBG of control group and metformin receiving groups compared to untreated type II diabetic rats (b). Each experiment was repeated independently three times in triplicate tests and data are shown as mean ± SEM. ***P ≤ 0.001

Effect of 8 IU/day insulin administration on CYP2D1 activity

As it was expected, the FBG levels in insulin received type I diabetic group was significantly decreased in comparison to untreated group (110 ± 16 mg/dl vs 471 ± 32 mg/dl) (p˂ 0.001) (Fig. 3a) and also there was an increase in enzyme activity following two weeks of insulin administration in treated group in comparison to untreated ones, in which the mean metabolic ratio was changed from 0.006 ± 0.001 in the untreated diabetic rats to 0.008 ± 0.001 in treated ones (p˂ 0.05) (Fig. 1a). This improvement was not enough to reach to the observed levels of enzyme activity in control group (p˂ 0.05).

Effect of treatment with 8 IU/day insulin on hepatic clearance

Comparison of DM hepatic clearance in different groups demonstrated reduction of calculated parameter in type I diabetic rats compared to control group (5.2 ± 0.2 vs 6.3 ± 0.1) (p˂ 0.001). Although hepatic clearance has increased in insulin receiving group (5.4 ± 0.1) in comparison to untreated ones, this enhancement was not enough to reach to observed hepatic clearance levels in the control group (p˂ 0.001) (Fig. 2a).

Fig. 2.

Fig. 2

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Clearance profile (based on 3 endpoints of dextromethorphan concentrations) in all type I diabetic groups compared to control rats, following the passage of the perfusion buffer containing 300 μM dextromethorphan through the portal vein (mean ± SEM) (a). Clearance profile (based on 3 endpoints of dextromethorphan concentrations) in all type II diabetic groups compared to control rats, following the passage of the perfusion buffer containing 300 μM dextromethorphan through the portal vein (mean ± SEM) (b). Each group contains 4 rats. Data are shown as mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001

Effect of type II diabetes on CYP2D1 activity

The average of FBG levels in untreated rats was significantly increased compared to control group (269 ± 17 mg/dl vs 75 ± 4 mg/dl), approving induction of the diabetes type II in animal model. (Fig. 3b). Even though, the mean metabolic ratio was reduced from 0.012 ± 0.004 in the control group to 0.008 ± 0.003 in the untreated diabetic rats, the observed reduction was not statistically significant (p˃ 0.05) (Fig. 1b).

Effect of 200 mg/kg metformin administration on CYP2D1 activity

As it has been predictable, the FBG levels in metformin receiving diabetic group was decreased in comparison to untreated rats (269 ± 17 mg/dl vs 154 ± 12 mg/dl) and this modulation was statistically significant (p˂ 0.001) (Fig. 3b). Surprisingly, the mean metabolic ratio was increased from 0.008 ± 0.003 to 0.013 ± 0.003 in the untreated diabetic rats against treated ones (Fig. 1b). So, the observed data demonstrated that metformin administration in diabetic rats could rebalance the metabolic activity in which no significant difference in CYP2D1 activity was observed in treated groups within controls (p˃ 0.05).

Effect of 200 mg/kg metformin administration on CYP2D1 activity in control group of healthy rats

In order to find out that if metformin itself has any induction on CYP2D1 activity, another group was added to the study, receiving metformin by control group of healthy animals.

Even though slightly increased enzyme activity was observed in the control group of healthy rats receiving metformin compared to the control group (0.013 ± 0.002 vs 0.012 ± 0.004), the observed trend was not statistically significant (p˃ 0.05) (Fig. 1b).

The FBG levels of control group of healthy rats receiving metformin (69 ± 3 mg/dl) was not statistically different (p˃ 0.05) from control group (75 ± 4 mg/dl) which is in accordance with other findings that hypoglycemia rarely happens due to metformin administration in non-diabetics (Fig. 3b) (30).

Effect of treatment with 200 mg/kg metformin on hepatic clearance

Although the hepatic clearance of DM was significantly decreased in diabetic group ((5.0 ± 0.6 vs 6.3 ± 0.1), p˂ 0.01), the calculated parameter in metformin receiving group demonstrated a substantial modulating effect of metformin in which no statistical difference was observed in comparison to controls with p value of about 0.493 (6.3 ± 0.1 vs 6.1 ± 0.4) (Fig. 2b).

In line with evaluation of possible effects of metformin in control group of healthy rats, administration of metformin to this group has not changed hepatic clearance in comparison to control group (CL = 6.3 ± 0.2 vs 6.1 ± 0.4) (p˃ 0.05) (Fig. 2b).

Discussion

Although drug-drug interactions are becoming more predictable due to increasing knowledge about the effects of medications on drug-metabolizing enzymes (induction and inhibition), our understanding of the effect of disease states on drug metabolism processes has not been well enough. Many diseases, especially those could stimulate the inflammatory processes, are accompanied by one or more physiological and biochemical alterations in the absorption, distribution, metabolism, and elimination (ADME) of medicines [31]. These types of alterations can make some changes in the clearance, exposure, and distribution of medicines.

The liver is the main organ where drug metabolism of xenobiotics occurs followed by intestine and kidneys which are less important. [32, 33]. The cytochrome P450 (CYP) family of enzymes is by far the main biotransformation pathway for the majority of marketed medicines [13].

Nowadays, it was demonstrated that some diseases could alter the expression of oxidative enzymes or make change in their activities due to increasing level of some inflammatory cytokines such as IL-1β, IL-6 and TNF-α [34, 35].

Infections and many chronic diseases are known to be able to alternate the hepatic and extrahepatic biotransformation of drugs especially due to stimulate secretion of inflammatory cytokines [4, 36, 37].

In the present study, the effect of type I and type II diabetes on the activity of CYP2D1 and the hepatic clearance of diabetic rats was compared with that of control group. Additionally, the effect of insulin and metformin on the enzyme activity and hepatic clearance along with changes in blood sugar profile was investigated in the isolated rat perfused liver model. It should be noted that the isolation of the liver was performed one week after diabetes induction using STZ to minimize the effect of the induction method on the final decision and also to allow sufficient time for probable effect of diabetes on oxidative enzyme activity. Since it is very difficult to maintain diabetic rats without any treatment, differences in enzyme activity were evaluated one and two weeks after induction of diabetes and no significant differences were observed between the two groups. The effect of STZ on test conditions appears to be negligible after about one week (data was not shown). The results demonstrated that type I diabetes could significantly decrease the activity of CYP2D1 with respect to average metabolic ratios of three last sampling time points (p˂ 0.05) compared to control group. Fortunately, in line with the reduction of FBG levels in insulin receiving group, there was sign of significant modulation in the enzyme activity in treated rats in comparison with untreated ones (p˂ 0.05). It has been reported that the expression of hepatic CYP2D1 was not changed in streptozotocin induced diabetic rats [38]. So, it can be concluded that the reduction of dextromethorphan metabolism in diabetic rats in this study, is probably due to decrease of enzyme activity and not via suppression of enzyme’s mRNA expression and protein level.

Similarly, Type I diabetes mellitus significantly decreased the hepatic clearance of DM in untreated rats compared to control group (p˂ 0.05). Surprisingly, regardless of the modulation effects of insulin therapy on enzyme activity, this treatment was not capable of modulate the hepatic clearance in comparison with untreated group (p˃ 0.05). The inefficiency of insulin in rebalancing hepatic clearance could be described with several reasons in this study; including insufficient insulin administration during the treatment period, the wide time intervals used for medication (once daily) which both of them may lead to more fluctuations in blood glucose levels, the complexity of damages in microvascular system followed by diabetes induction that the administered dose was not be able to retrieve it. The last possible reason could be described by the human source of administered insulin which not only could not reduce the inflammation in treated rats, but also might induce inflammation and increased the level of inflammatory cytokines leading to unchanged hepatic clearance.

Unlike type I diabetes, although the results of mean metabolic ratios indicate a tendency to decrease in the enzyme activity associated with diabetes, no significant difference was observed in enzyme activity of the untreated diabetic rats compared to control group. These results are supported with a new study [39] which showed no alternation in CYP2D6 activity in patients with type II diabetes with the same probe that used in our study.

As it was mentioned, metformin administration in diabetic rats could reduce FBG levels as well as rebalance the CYP2D1 enzyme activity wherein no significant differences were observed in treated groups within controls. In order to better explanation of metformin effects on regulating the enzyme activity, another group was added to the study. For this purpose and under similar conditions, the same dose of metformin was administered to control group of healthy rats for two weeks. Even though, the average metabolic ratios showed a very slightly increase compared to the control group, there was no significant difference between the two groups. The rebalancing effects of metformin could be due to the inhibitory effect of metformin on some inflammatory cytokines such as TNF-α, IL-1β and IL-6 which has been proven to be one of the main reasons for suppressing CYP450 enzyme activity [40, 41]. It is difficult to discriminate between the positive effect of metformin on enzyme activity and the effect of blood glucose level due to lesser organ damage in type II diabetes. Although it has not been mentioned in this manuscript, further research was designed in this regard which the proposed positive effect of metformin on metabolic enzyme activity was assessed in type I diabetic rats regardless of not having positive effect on reduction of blood glucose levels (data was not shown). Besides our team has begun evaluation of the effect of type 2 diabetes mellitus on important CYP450 enzyme isoforms (e.g. CYP3A4, CYP2D6, CYP2C9, CYP2C19) and P-gp activities, before and after glycemic control in patients with type 2 diabetes in order to assess the result of our animal studies and find out if these results have correlation with human subjects and gain better understanding of the effect of diabetes mellitus on the pharmacokinetic parameters, specially metabolism of human [42].

Although any rebalancing effect of insulin treatment on hepatic clearance of DM was not observed in type I diabetic rats, metformin administration could modulate this parameter to the mean calculated levels in control group. This observation may also be explained by anti-inflammatory effects of metformin; as the microvascular complications in type II diabetes are less than the other type.

Conclusion

In general, the results of this study demonstrated that reduction in CYP2D1 activity in type I diabetes and also decrease in hepatic clearance due to type I and type II diabetes mellitus can occur; which confirms the “phenoconversion” hypothesis associated with inflammatory diseases and makes it necessary to consider the level of metabolic activity of the enzymes, especially when prescribing the drugs associated with this enzyme system. On the other hand, the observed modulation in enzymatic activity and hepatic clearance after treatment is another reason for the importance of continuous monitoring of the enzyme activity and hepatic clearance in diabetic patients with the aim of increasing therapeutic effects and reducing the side effects of polypharmacy.

Acknowledgements

This work was fully supported by a grant from National Institute for Medical Research Development of Iran (NIMAD) (grant no. 957596). The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest.

Footnotes

Publisher’s note

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