ABSTRACT
Introduction:
Proton pump inhibitors (PPIs) are the most commonly used drug worldwide. PPIs are benzimidazole derivatives and are basic in nature; therefore, they are dispensed in enteric-coated tablets or capsules to avoid degradation from gastric acid. When PPIs are administered by oral route of administration, they get absorbed from small intestine and cross the acidic parietal cell canaliculus. In this acidic environment, PPI is activated and produces a sulfenamide form of the drug. This activated form binds with the H+ K+ ATPase enzyme covalently, which results in irreversible inhibition of acid secretion
Aim:
Study to establish the relationship between rabeprazole (PPI) and acute interstitial nephritis (AIN).
Objective:
To find the effect of PPI alone, PPI with diclofenac, PPI with ofloxacin on renal function tests.
Methods:
In the present study, we are analyzing PPI (omeprazole) as a main group. The group is again divided into three subgroups containing six rats in each. The relation between PPI and AIN is observed by the administration of PPI alone. To find this relation, we combine the PPI with nonsteroidal anti-inflammatory drug (NSAID) diclofenac and antimicrobial agent ofloxacin.
Results:
Rabeprazole 20 mg/kg/day alone showed a statistically significant difference in serum creatinine and blood urea values. Rabeprazole 20 mg/kg/day and ofloxacin 60 mg/kg/day did not show a statistically significant difference in serum creatinine and blood urea values. Rabeprazole 20 mg/kg/day and diclofenac showed a statistically significant difference in serum creatinine and blood urea values.
Conclusion:
With longer administration of PPIs, it did produce derangement of renal function tests (RFTs), and with concurrent administration of drugs like ofloxacin and diclofenac, it hastened the process of renal damage as indicated by deranged RFTs.
KEYWORDS: AIN, diclofenac, ofloxacin, proton pump inhibitors
INTRODUCTION
Proton pump inhibitors (PPIs) are the most commonly used drug worldwide. PPIs are benzimidazole derivatives and are basic in nature; therefore, they are dispensed in enteric-coated tablets or capsules to avoid degradation from gastric acid. When PPIs are administered by oral route of administration, they get absorbed from the small intestine and cross the acidic parietal cell canaliculus. In this acidic environment, PPI is activated and produces a sulfenamide form of the drug. This activated form binds with the H+ K+ ATPase enzyme covalently, which results in irreversible inhibition of acid secretion. Though the half-life of these drugs is short, the effect remains for a longer duration as the parietal cell must have to produce newer proton pumps to release the gastric acid into the stomach.[1]
In 1996, around 1.7 million prescriptions of PPI were dispensed in Australia,[2] while till 2006, it was the third most frequently prescribed drug.[3] In United States, only esrabeprazole (Nexium™) was the second-ranked medicine sold in 2014 by price with 5,97,45,50,000 US dollars,[2] and by units prescribed, it was the fifth-ranked medication with 2,35,18,000 units;[4] other PPIs are not included in this. In New Zealand, till 2013 42.8% prescriptions of rabeprazole for registered patients were dispensed, which make it third most widely prescribed drug.[5] Similarly several drug utilization studies were carried out in India, which show that the use of proton pump inhibitors varies from 45 to 85% in different conditions.[6,7,8] In 82.96% of patients suffering from chronic renal disease, PPI was used.[9] Another study of intravenous PPI utilization shows that 89% of internal medicine ward patients and 34.04% of patients in surgery ward PPI were used.[10]
MATERIAL METHODS
In the present study, we analyze PPI (omeprazole) as a main group. The group is again divided into three subgroups containing six rats in each.
The relation between PPI and AIN is observed by the administration of PPI alone. To find this relation, we combine the PPI with nonsteroidal anti-inflammatory drug (NSAID) diclofenac and the antimicrobial agent ofloxacin.
The total sample size for the study is 18 Wistar rats. Healthy Wistar rats were included in the present study.
Rats with a weight of 150–250 grams and with an age of 180–220 days will be included.
Rats with deranged renal function test at 0 days will be excluded from the study. Simple random sampling will be used for the randomization. Wistar rats will be numbered and will be divided into subgroups with the help of random number tables.
In this animal study, the researcher plans to collect blood by retro-orbital blood withdrawal technique with aseptic precautions. Blood will be collected on the 0th day (before giving the drug) and 28th day.
The collected blood will be analyzed for RFTs:
Serum Creatinine.
Blood Urea.
RESULTS AND OBSERVATIONS
Effect of rabeprazole on RFTs
Rabeprazole 20 mg/kg/day alone did not show a statistically significant difference in serum creatinine and blood urea values between the 0th day and 28th day [Tables 1-6]. Rabeprazole 20 mg/kg/day alone showed a statistically significant difference in blood urea values between the 0th day and 28th day.
Table 1.
Effect of rabeprazole 20 mg/kg/day on serum creatinine
| n | Mean±SD | t | P | |
|---|---|---|---|---|
| 0th day | 6 | 0.65±0.11 | 0.49 | 0.647 |
| 28th day | 6 | 0.68±0.05 |
Table 6.
Effect of rabeprazole 20 mg/kg/day and diclofenac on blood urea
| n | Mean±SD | t | P | |
|---|---|---|---|---|
| 0th day | 6 | 37.79±4.64 | 2.48 | 0.056 |
| 28th day | 6 | 51.02±15.16 |
Table 2.
Effect of rabeprazole 20 mg/kg/day on blood urea
| n | Mean±SD | t | P | |
|---|---|---|---|---|
| 0th day | 6 | 34.69±5.13 | 3.26 | 0.022 |
| 28th day | 6 | 45.86±4.36 |
Table 3.
Effect of rabeprazole 20 mg/kg/day and Ofloxacin 60 mg/kg/day on serum creatinine
| n | Mean±SD | t | P | |
|---|---|---|---|---|
| 0th day | 6 | 0.65±0.13 | 1.54 | 0.185 |
| 28th day | 6 | 0.73±0.05 |
Table 4.
Effect of rabeprazole 20 mg/kg/day and ofloxacin 60 mg/kg/day on blood urea
| n | Mean±SD | t | P | |
|---|---|---|---|---|
| 0th day | 6 | 37.67±4.53 | 0.57 | 0.593 |
| 28th day | 6 | 36.05±4.79 |
Table 5.
Effect of rabeprazole 20 mg/kg/day and diclofenac on serum creatinine
| n | Mean±SD | t | P | |
|---|---|---|---|---|
| 0th day | 6 | 0.63±0.12 | 2.50 | 0.054 |
| 28th day | 6 | 0.80±0.06 |
Rabeprazole 20 mg/kg/day and ofloxacin 60 mg/kg/day did not show a statistically significant difference in serum creatinine and blood urea values between the 0th day and 28th day.
Rabeprazole 20 mg/kg/day and diclofenac did not show a statistically significant difference in serum creatinine and blood urea values between the 0th day and 28th day.
DISCUSSION
In an animal experimental study, we found that in the dose of rabeprazole 20 mg/kg/day there is a significant difference in the serum creatinine levels before and after the last administration of the drug. The drugs that were used were obtained from standard sources and animal doses were extrapolated from human doses.
We observed in all cases of AIN that variable degree of vascular damage and inflammatory response, leading to structural damage, was present. As seen in our study, though the groups were homogenous not all animals suffered from this problem. As postulated[2,11] by some researchers, this can be attributed to idiosyncratic reaction.
It is possible to infer that if we would have stopped the drug at the first confirmed sign of deranged renal function, we could have seen a reversal of the damage and confirmation of the postulate.[2,11,12]
The increased levels of IL-18 in the posttest than the pretest are seen significant which is also supported by the histopathological studies that inflammatory changes are seen in most of the animals’ kidneys.
CONCLUSION
With longer administration of PPIs, it did produce derangement of renal function tests (RFTs), and with concurrent administration of drugs like ofloxacin and diclofenac, it hastened the process of renal damage as indicated by deranged RFTs.
Our study indicated that PPI alone was able to induce inflammatory process in the kidney along with deranged RFT. When PPIs were coadministered along with diclofenac or ofloxacin, the percentage of animals showing such an effect marginally increased. However, direct extrapolation of animal study results has limited importance; hence, longer and larger human pharmacovigilance data are needed.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
REFERENCES
- 1.Bruce TV, Rundsarah MT. Proton pump inhibitors:An update. Am Family Physician. 2002;6:273–80. 2. [PubMed] [Google Scholar]
- 2.McManus P, Marley, Birkett DJ, Lindner J. Compliance with restrictions on the subsidized use of proton pump inhibitors in Australia. Br J Clin Pharmacol. 1998;46:409–11. doi: 10.1046/j.1365-2125.1998.00791.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Geevasinga N, Patrik LC, Angela CW, Simon DR. Proton pump inhibitors and acute interstitial nephritis. Clin Gastro Hep. 2006;4:597–604. doi: 10.1016/j.cgh.2005.11.004. [DOI] [PubMed] [Google Scholar]
- 4.Proto pump inhibitors:When is enough, enough? Brit J Pharmacol issue. :8–15. [Google Scholar]
- 5.Raghvendra B, Sanji N, Ullal SD, Kamath R, Pain MRSM, Kamath S, et al. Trends in prescribing gastroprotective agents with non-steroidal anti- inflammatory drugs in an orthopedic outpatient unit of a tertiary care hospital. J Clin Diagn Res. 2009;3:1553–6. [Google Scholar]
- 6.Nouseen, Tadvi NA, Shareef SM. Use of proton pump inhibitors in general practice. Is it rationale? Int J Med Res Health Sci. 2014;3:37–42. [Google Scholar]
- 7.Kaur S, Rajagopalan S, Kaur N, Shafiq N, Bhalla A, Pandhi P, Malhotra S. Drug utilization study in medical emergency unit of a tertiary care hospital in North India. Emerg Med Int. 2014;2014:973578. doi: 10.1155/2014/973578. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Tamilselvan T, Veerapandiyan AK, Karthik N. Study on drug utilization pattern of chronic renal failure patient in a tertiary care hospital. Int J Pharm Sci. 2014;6:482–84. [Google Scholar]
- 9.Churi S, Jogani A. Prospective assessment of prescribing pattern of intravenous proton pump inhibitors in an Indian tertiary care teaching hospital. Indian J Pharm Pract. 2004;7:2–7. [Google Scholar]
- 10.Limaye RP, Pendhari SR, Joshi KS. Proton pump inhibitors:Are they safe on kidneys:A histopathological study. Int J Basic Clin Pharmacol. 2017;5:1187–92. [Google Scholar]
- 11.Ang SP, Chia JE, Valladares C, Patel S, Gewirtz D, Iglesias J. Association between proton pump inhibitor use and risk of incident chronic kidney disease:Systematic review and meta-analysis. Biomedicines. 2024;12:1414. doi: 10.3390/biomedicines12071414. doi:10.3390/ biomedicines12071414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. [[Last accessed on 2016 Jan 13]]; Available from: www.drug.com/stat/top100/2013/sales. [Google Scholar]
