|Year : 2021 | Volume
| Issue : 1 | Page : 57-63
Atorvastatin enhanced the bioavailability of irinotecan by inhibition of permeability-glycoprotein in rats with colon cancer: In vivo and in vitro studies
Kiran Lyagala, Prasad Neerati
Department of Pharmacology, Clinical Pharmacology Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana, India
|Date of Submission||21-Oct-2019|
|Date of Decision||25-Feb-2020|
|Date of Acceptance||12-Mar-2020|
|Date of Web Publication||27-Jan-2021|
Department of Pharmacology, Clinical Pharmacology Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Satins' combination with anticancer drugs is a potential combination in treating cancer, which also inhibits the permeability glycoprotein (P-gp) to reduce the development of drug resistance by altering the absorption kinetics. The objective of the present investigation was to study the effect of atorvastatin (ATS) and verapamil (VER) on the pharmacokinetics of irinotecan (IRT) by N-methyl N-nitroso-urea-induced cancer in rat colon and small intestine. Materials and Methods: An in vitro study using noneverted sac model was conducted to determine the effect of ATS on the functional status of intestinal P-gp in colon cancer-induced rats. IRT (75 μg/ml) with and without VER (200 μM) and ATR (30 μg/ml) were filled into the excised colon tissue. In in vivo study, VER (25 mg/kg, p.o.) and ATS (20 mg/kg, p.o.) were administered separately 2 h before IRT (80 mg/kg, p.o.) dosing in male Wistar rats. Serum samples were collected at 0.5, 1, 2, 4, 6, 8, 10, and 12 h time points from control and treated animals to determine IRT concentration. Results: An in vitro noneverted sac study indicated IRT to be a P-gp substrate, and the function of intestinal P-gp was significantly inhibited in the presence of VER and ATS. After oral TRT dosing, the mean area under the plasma concentration-time curve was found to be 1.406 ± 0.15, which was increased significantly, i.e., 2.376 ± 0.19 (P < 0.001) and 1.856 ± 0.07 (P < 0.01), when VER and ATS, respectively, were co-administered with IRT. Similarly, the mean maximum plasma concentration of IRT increased from 0.247 ± 0.02 μg/ml (IRT alone) to 0.390 ± 0.03 (P < 0.001) (with VER) to 0.321 ± 0.02 (P < 0.01) (with ATS). Conclusion: These results indicate the improved bioavailability of IRT by the P-gp inhibitory effect of ATS, and further investigation is needed to develop IRT oral formulation in combination with suitable P-gp inhibitors for the treatment of colon cancer.
Keywords: Atorvastatin, colon cancerous rats, in vitro, in vivo, irinotecan, permeability glycoprotein
|How to cite this article:|
Lyagala K, Neerati P. Atorvastatin enhanced the bioavailability of irinotecan by inhibition of permeability-glycoprotein in rats with colon cancer: In vivo and in vitro studies. J Nat Sc Biol Med 2021;12:57-63
|How to cite this URL:|
Lyagala K, Neerati P. Atorvastatin enhanced the bioavailability of irinotecan by inhibition of permeability-glycoprotein in rats with colon cancer: In vivo and in vitro studies. J Nat Sc Biol Med [serial online] 2021 [cited 2021 Mar 8];12:57-63. Available from: http://www.jnsbm.org/text.asp?2021/12/1/57/307852
| Introduction|| |
Drug–drug interactions can cause serious adverse events, especially in oncology, as a result of the narrow therapeutic window of most of the chemotherapeutic agents. Small changes in the pharmacokinetics (PK) or pharmacodynamics of chemotherapy caused by another drug can result in significant changes in its toxicity or efficacy. As cancer patients often experience disease and age-related organ failure, they undergo combinational drug therapy, which put them at risk for drug–drug interactions. Irinotecan (IRT) (CPT-11) is an antineoplastic agent primarily used in the treatment of metastatic colorectal cancer (CRC). It is chemically (S)-10-[4-(-piperidino) piperidinocarbonyl oxoyl]-4, 7-diethyl-4-hydroxy-1H-pyrano [3, 4:6, 7] indolizino [1,2-b] diethyl-3, 14 [4H, 12H]-dionemono hydrochloride trihydrate. It is a semi-synthetic, water-soluble derivative of camptothecin, which is a cytotoxic alkaloid extracted from plants such as Camptotheca acuminate. IRT is a prodrug which is converted in in vivo to active metabolite 7-ethyl-10-hydroxy camptothecin (SN-38) that is 100–1000 times more potent. IRT and its active metabolite, SN-38, inhibit the action of topoisomerase I, an enzyme that produces reversible single-strand breaks in DNA during DNA replication, resulting in double-strand DNA breakage and cell death. Majority of the studies conducted with IRT are using intravenous administration.,,, However, it has been given orally in early clinical studies, and it was proved that its PK profile is characterized by relatively poor and highly variable oral bioavailability.,,, The main adverse effects of IRT in humans are gastrointestinal toxicity and myelosuppression, which limit its usage., The involvement of active transporters, particularly permeability-glycoprotein (P-gp), in the transport of both IRT and SN-38 is demonstrated by various researchers.,,,, P-gp is the major efflux transporter protein responsible for poor absorption of many drugs. The oral absorption of IRT is limited by its poor absorption, which is attributed to its efflux by P-gp, a major efflux transporter protein. Presence of P-gp in the intestinal membrane limits the absorption of IRT,,,,, and P-gp inhibition is a logical strategy to enhance IRT's oral bioavailability and ameliorating diarrheal toxicities. Verapamil (VER) is the most extensively characterized P-gp inhibitor and multidrug resistance reversal agent that has entered clinical trials. It was also reported that VER has increased the area under the plasma concentration-time curve (AUC) of doxorubicin, IRT, and topotecan in rodents by blocking the P-gp-mediated efflux.,,,,
Mutations in the tumor suppressor gene, adenomatous polyposis gene (APG), result in uncontrolled proliferation of intestinal epithelial cells and are associated with the earliest stages of colorectal carcinogenesis. There are several mouse models for familial adenomatous polyposis (FAP) with different germline Apc mutation sites such as codons 716, 850, 1309, and 1638., It was previously reported that two strains of Apc gene-deficient mice, Min (Apc gene mutation at codon 850) and Apc1309 (mutated at codon 1309) mice, show particularly large numbers of intestinal polyps and a hyperlipidemic state. Hyperlipidemia was found to be a relatively frequent complication in FAP patients, suggesting its possible link to CRC development. Moreover, atorvastatin (ATS) co-administration may increase digoxin concentrations by the inhibition of intestinal P-gp-mediated secretion, thereby acting as a P-gp inhibitor. All these studies strongly support that statins might play a major role in the treatment of CRC, perhaps more as adjuvant agents to chemotherapy. The design of the present study was to conduct an initial in vitro noneverted sac model in rats so as to evaluate the effect of both VER and ATS on the function of intestinal P-gp. This was followed by the determination of IRT PK (plasma concentrations) following oral administration with and without co-administration of VER and ATS in male rats. Based on these studies, it might be feasible to reduce the dose of IRT by concomitant oral administration of VER or ATS with IRT in CRC treatment, and the risk of metabolic saturation with IRT could be substantially reduced because of reduced dose.
| Materials and Methods|| |
IRT was gifted by Dr. Reddy's Laboratories (Hyderabad, India). Camptothecin was gifted by Himalayan Herbs (Thane, Mumbai). VER was gifted by Matrix Laboratories Ltd. (Hyderabad, India). ATS was gifted by Aurobindo Pharma (Hyderabad, India). Phosphate buffered saline, MgCl2 and glucose were analytical grade. N-Methyl Nitroso Urea (MNU) (Sigma Aldrich, San Francisco, USA) and solvents used were of high-performance liquid chromatography (HPLC) grade, and all other chemical reagents were of analytical grade.
In vitro permeability studies
Healthy male Wistar rats (180–250 g) were used for in vitro noneverted sac model. Anesthesia, surgical, and disposal procedures and the animal experiments described herein were approved by the institutional animal ethics committee (IAEC/10/UCPSc/KU/2018, TS, Warangal, Telangana State, India), and the protocol complies with the recommendations of the committee. Prior approval for conducting the experiments in rats was obtained from our institutional animal committee. Following an overnight fasting, the rats were divided into four groups (n = 6). MNU (2 mg/kg) solution (0.5 ml) was administered through intrarectal route three times weekly for 12 weeks to induce intestinal and colon cancer. Histological studies were performed to confirm the induction of cancer in ileum and colon and then noneverted colon sacs were prepared and subjected to further analysis.
- Group I: IRT (30 μg/ml) loaded to normal colon sacs
- Group II: IRT (30 μg/ml) loaded to cancer colon sacs
- Group III: IRT (30 μg/ml) + VER (200 μM) loaded to cancer colon sacs
- Group IV: IRT (30 μg/ml) + ATS (30 μg/ml) loaded to cancer colon sacs.
Preparation of noneverted colon sacs
The experiment was performed according to the models described previously. Rats fasted overnight with free access to water were anesthetized by an intraperitoneal injection of thiopental (50 mg/kg). Upon the verification of loss of pain reflex, a midline incision of 3–4 cm was made, and the colon was located using colon–cecal junction as a proximal marker. The colon was washed with phosphate buffer at 37°C by peristaltic pump feeding. The cleaned colon was removed and was prepared into 10-cm-long sacs with a volume of 5 ml by ligation. Each sac was filled 5 ml of oxygenated buffer solution (containing 75 μg/ml IRT), and both ends were ligated. In case of pretreated groups, the respective drugs such as VER and ATS along with IRT were filled in the sac and the ends were ligated. Each noneverted sac was placed in a glass beaker (50 ml) containing 10 ml of oxygenated buffer solution. The sacs were maintained at 37°C in a shaking water bath operating at 100 strokes per min and constantly gassed with O2. Solution (10 ml) outside the sacs was taken every 10 min for 90 min and replaced with fresh buffer (10 ml). The contents of the samples were subjected to HPLC analysis.
Pharmacokinetic study (in vivo)
Animals and drug administration
Healthy male Wistar rats (180–250 g, n = 6) were used for PK study. Rats housed in cages were kept in a room under controlled temperature (20°C–22°C) and 12 h day–night cycle. Animals were used for PK studies after 1-week acclimatization with free access to water and feed. All animal procedures were approved by the institutional animal ethics committee (IAEC/10/UCPSc/KU/2018, TS, India). The dose of IRT (80 mg/kg/oral) was selected based on the existing reports.,, VER dose (25 mg/kg/oral) was selected in reference to the existing reports., The dose of ATS was selected (20 mg/kg/oral) based on the existing reports. Following an overnight fasting, the rats were divided into four groups (n = 6).
- Group I: IRT (80 mg/kg; p.o.) in normal rats
- Group II: IRT (80 mg/kg; p.o.) in cancerous rats
- Group III: IRT (80 mg/kg; p.o.) + VER (25 mg/kg; p.o.) in cancerous rats
- Group IV: IRT (80 mg/kg; p.o.) + ATS (20 mg/kg; p.o.) in cancerous rats.
Blood samples (0.4 ml) were withdrawn prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, and 12 h postdosing from retro-orbital plexus. Serum was obtained by centrifuging at 10,000 rpm for 10 min. Samples were stored at −80°C until HPLC analysis.
Determination of irinotecan by high-performance liquid chromatography
A method using reverse-phase (RP)-HPLC with an ultraviolet detector was developed and validated for the analysis of IRT in rat serum. HPLC was conducted on Schimadzu (Kyoto, Japan). The column used for chromatographic separations was of 4.6 mm, i.e., 250 mm length and 5 μm particle size C18 (Merck, India). An aliquot of 20 μl was injected onto a C18 column. For the analysis of IRT, the mobile phase composed of 65% phosphate buffer and 35% acetonitrile (pH adjusted to 2.5 with orthophosphoric acid) was pumped at a flow rate of 1 ml/min, and the chromatogram was recorded at 225 nm.,, The total run time for each sample was 15 min. All the analytes, namely, camptothecin and IRT, were well separated with retention times of 8.77 min and 4.94 min, respectively, for in vitro and 10.33 min and 7.14 min, respectively, for in vivo. In in vivo study, serum proteins were precipitated by the addition of ice cold 10 μg/ml camptothecin (internal standard) in acetonitrile containing 0.1% glacial acetic acid (1:1 ratio). After rigorous vortex mixing for 5 min, the mixtures were centrifuged at 10,000 rpm for 10 min. The supernatant was transferred to a fresh tube and 20 μl was injected onto the column for analysis.
Calculation of apparent permeability
The apparent permeability co-efficient (Papp) of drugs was calculated from the following equation:
where dQ/dt is the steady-state appearance rate on the acceptor solution, A is the surface area of intestinal sacs, and Co is the initial concentration inside the sac.
PK parameters were calculated using KINETICA software (San Francisco, USA). The plasma IRT concentration versus time curves were used to determine maximum plasma concentration (Cmax), time to achieve maximum plasma concentration (Tmax), AUC to the respective sampling point (AUC0-12), half-life (t1/2), and total body clearance.
All the data were expressed as mean ± standard deviation, and sample comparisons were performed using one-way ANNOVA (Dunnetts test). The whole statistical analysis was done using Graph Pad version 5.0 (California, USA).
| Results|| |
In vitro study
Cancer induction was done by standard procedure with MNU in ileum and colon [Figure 1] and [Figure 2]. The permeability of IRT was determined in rat colon segment using noneverted sac model, and the samples were analyzed by RP-HPLC. Apparent permeability values were calculated. The apparent permeability coefficient of IRT in normal and colon cancer-induced rats was found to be 0.0004765 cm/s and 0.000275 cm/s, respectively [Figure 3]a. The apparent permeability of IRT in the presence and absence of VER was found to be 0.00291 cm/s and 0.000275 cm/s, respectively [Figure 3]b. The apparent permeability of IRT was found to increase by 10.5-fold when VER (200 μM) was given along with IRT. The apparent permeability coefficient of IRT in the absence and presence of ATS (30 μg/ml) was found to be 0.000275 cm/s and 0.001722 cm/s, respectively. There was a significant increase in colon permeability coefficient of about 6.25-fold when ATS (30 μg/ml) was given along with IRT.
|Figure 1: Male Wistar rats were administered with N-Methyl Nitroso Urea (2 mg/kg/intrarectal) three times weekly for 12 weeks to induce (ilium) small intestinal cancer. Mean ± standard deviation; ***Significant at P < 0.001; **Significant at P < 0.01; *Significant at P < 0.05 compared to normal rats. Statistical analysis was performed using unpaired t-test|
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|Figure 2: Male Wistar rats were administered with N-Methyl Nitroso Urea (2 mg/kg/intrarectal) three times weekly for 12 weeks to induce colon cancer. Mean ± standard deviation; ***Significant at P < 0.001; **Significant at P < 0.01; *Significant at P < 0.05 compared to normal rats. Statistical analysis was performed using unpaired t-test|
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|Figure 3: (a) Apparent permeability coefficient in normal and colon cancer rats (b) Effect of atorvastatin and verapamil on the apparent permeability of irinotecan (c) Pharmacokinetics in normal and colon cancer rats. Plasma concentration–time curves in normal and colon cancer rats (d) Pharmacokinetics of irinotecan in the absence and presence of verapamil and also in the absence and presence of atorvastatin. Plasma concentration–time curves of irinotecan rats. ***P < 0.001 and *P < 0.05, in comparison to control. Statistical analysis was performed using one-way ANOVA (Dunnett test)|
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In vivo study
Pharmacokinetics of irinotecan in the presence and absence of permeability glycoprotein modulators
Plasma concentration versus time curves of IRT in normal and cancerous rats are shown in [Figure 3]c, wherein the Cmax of IRT decreased in cancerous rats when compared to that of normal rats. Further, Cmax of IRT increased with both the ATS and VER [Figure 3]d. The PK parameters of IRT are mentioned in [Table 1]. After an initial absorption phase, the plasma concentrations of IRT declined gradually. ATS and VER administration was associated with an increase in IRT plasma concentrations following oral administration [Table 2]. Oral IRT concentrations increased significantly, leading to pronounced alteration in the PK. The IRT AUC increased from 1.429 ± 0.148 to 2.230 ± 0.087 h μg/ml (P < 0.001) with VER and 1.429 ± 0.148 to 1.783 ± 0.070 h μg/ml (P < 0.001) with ATS. The clearance decreased from 57.416 ± 6.603 to 33.850 ± 2.678 l/h (P < 0.001) with VER and 57.416 ± 6.603 to 43.149 ± 1.809 l/h (P < 0.01) with ATS, and there was a significant increase in Cmax from 0.247 ± 0.0278 to 0.390 ± 0.0349 (μg/ml) (P < 0.001) with VER and 0.247 ± 0.0278 to 0.321 ± 0.0278 (μg/ml) (P < 0.05) with ATS.
|Table 1: Mean pharmacokinetic parameters of irinotecan (80 mg/kg, p.o) in normal and cancerous rats|
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|Table 2: Mean pharmacokinetic parameters of irinotecan in the presence of verapamil and atorvastatin in cancerous rats|
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| Discussion|| |
IRT, a Food and Drug Administration-approved anticancer agent, is the most widely used antineoplastic drug in the treatment of various malignancies such as CRC and ovarian cancer. IRT belongs to Biopharmaceutics Classification System (BCS) Class II drug; in spite of its high permeability and low solubility, it has a low bioavailability profile because it is a P-gp substrate and the drug is being effluxed by the intestinal P-gp. For this reason, IRT is currently marketed for intravenous use, but a very few reports of its oral administration exist.,,, P-gp levels are higher in intestinal epithelium and in the epithelium of colon and jejunum. Various reports also showed that the bioavailability of many drugs is decreased due to the P-gp-mediated efflux occurring in small intestine.,,, Hence, the permeability of IRT is expected to alter in colon cancer. Therefore, an attempt was made to improve the low and erratic absorption of IRT by inhibiting P-gp-mediated efflux. Intestinal permeability is the propensity of a compound to move across the epithelial barrier of intestine. In vitro and in situ absorption models such as Caco-2 cell monolayer model, MDCK cell line, noneverted sac and everted sac models, and in situ perfusion of rat intestine are most commonly used to assess transport mechanism and permeability and to predict the absorption of drugs in human. It has been previously reported that VER as a P-gp inhibitor improves the intestinal permeability of paclitaxel (P-gp substrate) in rats by blocking the P-gp-mediated efflux. Thus, the increase in IRT intestinal permeability with VER is attributable to the P-gp-modulating ability of VER. These results indicated that P-gp limits the intestinal permeability of IRT by extruding it back to the intestine.
In addition, to a potential chemopreventive effect, statins might also interfere with CRC by inhibiting the ability of cancer cells to metastasize, as it has been reported that, among patients diagnosed with CRC, statin users had a 30% decreased prevalence of metastasis compared to statin nonusers. It has been shown that pretreatment of different colon cancer cell lines with lovastatin significantly increases apoptosis induced by 5-fluorouracil (5-FU) or cisplatin, an effect described in both drug-sensitive and drug-resistant cell lines. A recent case–control study of 1309 men with a new diagnosis of CRC (mean age 69 ± 1.1 [standard error] years; 326 statin users, 983 statin nonusers) suggested that in patients who presented to hospital with CRC, long-term use of statins was associated with less advanced tumor stage, a lower frequency of distant metastases, and an improved 5-year survival rate. Recent reports suggest that statins might reduce the risk of rectal cancer by as much as 50%., They might also enhance the efficacy of 5-FU in colon cancer. In CRC, loss of the low-density lipoprotein receptor on tumor cells is associated with a worse prognosis and higher HMG CoA reductase activity. Therefore, statins might effectively inhibit a molecular target associated with an adverse prognosis in a complementary way to standard combined modality therapy for rectal cancer.,, In our present in vivo study, the results showed that the PK of IRT got altered when they are given in combination with VER and ATS in cancerous rats. The PK parameters of IRT after oral administration were significantly different between normal and cancerous rats. All the PK parameters except Tmax, t1/2, and (Mean Residance Time) MRT were significantly decreased in cancerous rats when compared to normal rats. This significant change was attributed to the P-gp-mediated efflux of the drug, which is more in cancerous rats, leading to the significant decrease in almost all the PK parameters.
When IRT was given in combination with VER in cancerous rats, Cmax, AUCo-n, AUCtotal, AUMCtotal, and AUMC0-12 significantly increased due to P-gp inhibition, resulting in increased bioavailability of IRT. When IRT was given in combination with ATS in cancerous rats, Cmax, AUCo-n, AUCtotal, AUMCtotal, and AUMC0-12 significantly increased due to significant P-gp inhibition, resulting in increased bioavailability of IRT. In vitro studies by noneverted sac model using rat colon segment suggested that the permeability coefficient differences of IRT in normal colon of a rat when compared to the cancerous colon significantly increased. This is because of increased P-gp count in cancerous conditions resulting in the decreased permeability coefficient of IRT in cancerous colon in comparison to normal colon. The colon permeability coefficient of IRT for cancer control was found to be 0.000275 cm/s and for VER, it was found to be 0.00468 cm/s. VER (200 μM), a P-gp inhibitor, given along with IRT (30 μg/ml) resulted in significant increase in colon permeability by 10.5-fold (from 0.000275 to 0.00291 cm/s). The colon permeability coefficient of IRT in the absence and presence of ATS (30 μg/ml) was found to be 0.000275 cm/s and 0.001722 cm/s, respectively. A significant increase in colon permeability coefficient of about 6.25-fold was observed. All these results indicated that P-gp limits the colon permeability of IRT.
| Conclusion|| |
The results of increased bioavailability of IRT with VER and ATS suggest an interaction, which may be due to the decreased efflux of IRT by P-gp. The interaction of statins with anticancer drugs is of great importance as it may significantly influence the effectiveness of cancer treatments. Therefore, the combined treatment of tumors with statins and anticancer drugs is an area of research that warrants future study. Concomitant oral administration of VER with IRT in cancer treatment would allow dose reduction and more importantly, the risk of metabolic saturation with IRT could be substantially reduced. Hence, the present investigation warrants further studies to find out the relevance of this combination in human beings.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]