The role of organic cation transporter 2 inhibitor cimetidine, experimental diabetes mellitus and metformin on gabapentin pharmacokinetics in rats

Benzi, Jhohann Richard de Lima; Yamamoto, Priscila Akemi; Stevens, Hanna E.; Baviera, Amanda Martins; Moraes, Natália Valadares de

doi:10.1016/j.lfs.2018.03.012

Cited by 6 publications

(8 citation statements)

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“…Although GBP has been described as an OCT2 substrate, 43,44 the interaction with OCT2 is not relevant at therapeutic drug concentrations 45 . No significant changes in GBP kinetic disposition were observed after the coadministration of cimetidine (a known inhibitor of OCT2) or metformin (a known substrate of OCT2) in rats 60 . Moreover, cetirizine, an inhibitor of OCT2, MATE1 and 2‐K, 68,69 reduced the systemic exposure to GBP with no changes in renal clearance in patients with neuropathic pain, suggesting an interaction in the oral absorption process mediated by active transport (probably OCTN1) and not by renal drug transporters 45 .…”

Section: Discussionmentioning

confidence: 99%

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Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control

Costa

Benzi

Yamamoto

et al. 2020

Brit J Clinical Pharma

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Aims: Gabapentin (GBP) is widely used to treat neuropathic pain, including diabetic neuropathic pain. Our objective was to evaluate the role of diabetes and glycaemic control on GBP population pharmacokinetics. Methods: A clinical trial was conducted in patients with neuropathic pain (n = 29) due to type 2 diabetes (n = 19) or lumbar/cervical disc herniation (n = 10). All participants were treated with a single oral dose GBP. Blood was sampled up to 24 hours after GBP administration. Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm. Weight, body mass index, sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 (rs316019) and SLC22A4 (rs1050152), the genes encoding the transporters for organic cations OCT2 and OCTN1, were tested as potential covariates. Results: GBP drug disposition was described by a 1-compartment model with lagtime, first-order absorption and linear elimination. The total clearance was dependent on estimated glomerular filtration rate. Population estimates (between-subject variability in percentage) for lag time, first-order absorption rate, apparent volume of distribution and total clearance were 0.316 h (10.6%), 1.12 h −1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No significant association was observed with hyperglycaemia, glycated haemoglobin, diabetes diagnosis, age, sex, weight, body mass index, SLC22A2 or SLC22A4 genotypes. Conclusion: This population pharmacokinetics model accurately estimated GBP concentrations in patients with neuropathic pain, using estimated glomerular filtrationrate as a covariate for total clearance. The distribution and excretion processes of GBP were not affected by hyperglycaemia or diabetes.

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Section: Discussionmentioning

confidence: 99%

“…45 No significant changes in GBP kinetic disposition were observed after the coadministration of cimetidine (a known inhibitor of OCT2) or metformin (a known substrate of OCT2) in rats. 60 Moreover, cetirizine, an inhibitor of OCT2, MATE1…”

Section: Poppk Modellingmentioning

confidence: 99%

Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control

Costa

Benzi

Yamamoto

et al. 2020

Brit J Clinical Pharma

Self Cite

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“…14 The lamotrigine Summary of Product Characteristics contains advice that co-administering lamotrigine and organic cation transporter 2 (OCT2) substrates such as GBP, can cause increased plasma levels because lamotrigine has been found to inhibit OCT2 in vitro. 32,33 We found no statistical difference in the C/D ratio of GBP in patient using and not using lamotrigine. 32,33 We found no statistical difference in the C/D ratio of GBP in patient using and not using lamotrigine.…”

Section: Pharmacokinetic Variability From Retrospective Tdm Datamentioning

confidence: 58%

“…31 However, a possible role of OCT2 in GBP excretion is uncertain. 32,33 We found no statistical difference in the C/D ratio of GBP in patient using and not using lamotrigine.…”

Section: Pharmacokinetic Variability From Retrospective Tdm Datamentioning

confidence: 58%

Therapeutic drug monitoring of gabapentin in various indications

et al. 2019

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Objectives Gabapentin has been increasingly used in various indications in recent years. Despite variable pharmacokinetics, therapeutic drug monitoring (TDM) is scarcely described in other indications than epilepsy. The aim of the study was to investigate the use and pharmacokinetic variability of gabapentin in epilepsy and non‐epilepsy indications and to further evaluate the use of TDM in patients with restless legs syndrome (RLS). Materials & Methods Population‐based data from the Norwegian Prescription Database, retrospective TDM data from the section for Clinical Pharmacology, the National Center for Epilepsy, Norway, and prospective observational data on patients with RLS were used. Results The use of gabapentin increased by 30% from 2014 to 2017 (32 181 to 42 675 users). TDM data from 120 patients showed a 22‐fold pharmacokinetic variability in concentration/dose ratios, and this ratio was elevated in elderly patients (≥65 years). The majority of elderly used gabapentin for non‐epilepsy indications. In patients with RLS, intake in the evening/night only was common due to nocturnal symptoms, in contrast to regular dosing regimens in epilepsy. Thus, drug fasting concentrations do not reflect concentrations at the time of required therapeutic effect. TDM was still found useful in most patients to support dosage increase or evaluate adverse effects. Conclusion Due to extensive pharmacokinetic variability, TDM can benefit patients using gabapentin. Challenges with applying TDM in new indications such as RLS include different dosage regimens and consequently different interpretation of serum concentrations. Thus, TDM should be requested on clear clinical grounds and the service tailored according to the therapeutic indication.

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“…Increased renal clearance of GBP was observed in rats with experimental diabetes induced by streptozotocin [57], suggesting that the effects of diabetes on the kinetic disposition of GBP occurred by inducing glomerular hyperfiltration [58]. While the experimental model of diabetes follows a strict protocol in rats in terms of duration of the disease, this clinical study includes patients with different levels of renal function and duration of diabetes.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of gabapentin in patients with neuropathic pain: the role of glycaemic control

Costa¹,

Benzi²,

Yamamoto³

et al.

Authorea

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Aims: Gabapentin (GBP) is an α2-δ ligand drug widely used to treat neuropathic pain, especially diabetic neuropathy. The drug presents a saturable absorption in therapeutic doses and it is mainly eliminated unchanged in the urine. GBP excretion has been suggested to be dependent on glomerular filtration rate and active transport by renal drug carriers. Our objective was to evaluate the role of diabetes and glycaemic control on GBP pharmacokinetics using a population pharmacokinetic modelling approach. Methods: A clinical trial was conducted in participants with neuropathic pain of intensity [?] 4 evaluated by visual analogue scale (VAS) (n=29), due to lumbar or cervical disc herniation or due to diabetic neuropathy. All participants were treated with a single oral dose of 300 mg GBP. Blood samples were collected up to 24 hours after GBP administration. A population pharmacokinetic analysis was conducted to evaluate the inter-individual variability considering as potential covariates weight, height, body mass index (BMI), sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 and SLC22A4, the genes encoding the transporters for organic cations OCT2 and OCTN1. Results: Population estimates for lag time, first-order absorption rate, total clearance and apparent volume of distribution at steady state were 0.32 h, 1.13 h-1, 14.7 L/h and 140 L, respectively. The total plasma clearance of GBP is affected by the estimated glomerular filtration rate and the volume of distribution increases with higher glycaemic levels. Conclusion: GBP population pharmacokinetics was affected by renal function and glycaemic control.

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The role of organic cation transporter 2 inhibitor cimetidine, experimental diabetes mellitus and metformin on gabapentin pharmacokinetics in rats

Abstract: Glomerular filtration is the main mechanism of renal excretion of GAB without significant contribution of Oct2 active transport.

Cited by 6 publications

References 49 publications

Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control

Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control

Therapeutic drug monitoring of gabapentin in various indications

Population pharmacokinetics of gabapentin in patients with neuropathic pain: the role of glycaemic control

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