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Influence of aprepitant on the pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits.

ABSTRACT: Background:Concomitant drug administration is a general phenomenon in patients with chronic diseases such as diabetes mellitus. Among the currently available oral antidiabetic drugs, gliclazide is a commonly prescribed drug considering its multiple benefits in diabetic patients. Aprepitant is a commonly prescribed antiemetic drug which is mainly metabolized by CYP3A4, reported to have modest inductive and inhibitory effects on CYP2C9 and CYP3A4, respectively. Since gliclazide is metabolized by CYP2C9 (major) and CYP3A4 (minor), it is very difficult to predict the influence of aprepitant and its metabolic interaction with gliclazide. Considering the complexity associated with the combination of aprepitant and gliclazide, this study was designed to evaluate the influence of aprepitant on the pharmacodynamics (PD) and pharmacokinetics (PK) of gliclazide in animal models. Methods:The PD interaction studies were conducted in both rodent (normal and alloxan-induced diabetic rats) and non-rodent (rabbits) animal models (n = 6) while the PK interaction study was conducted in normal rabbits (n = 6). An extrapolated human therapeutic oral dose of gliclazide, aprepitant and their combination were administered to rats and rabbits with 7 days washout between each treatment. For the multiple-dose interaction study, the same groups were administered with an interacting drug (aprepitant) for 7 days and then the combination of aprepitant and gliclazide on the 8th day. From the collected animal blood samples, blood glucose (by Glucose-Oxidase/Peroxidase method), insulin (by ELISA method) and gliclazide concentration levels (by HPLC method) were determined. Non-compartmental PK analysis was conducted by Phoenix WinNonlin software to determine the PK parameters of gliclazide. Statistical analysis was performed by student's paired t-test. Results:The pharmacodynamic activity (blood glucose reduction and insulin levels) of gliclazide was significantly (p < 0.05) influenced by aprepitant in normal and diabetic condition without any convulsions in animals. There was a significant (p < 0.05) increase in concentration levels and Area Under the Curve of gliclazide while significant (p < 0.05) decrease in clearance levels of gliclazide in rabbits. The PK interaction with gliclazide is relatively more with the multiple dose treatment of aprepitant over single dose treatment. Conclusion:In combination, aprepitant significantly influenced the pharmacodynamic activity of gliclazide in animal models. Considering this, care should be taken when this combination is prescribed for the clinical benefit in diabetic patients.

SUBMITTER: Kura RR

PROVIDER: S-EPMC5969050 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Influence of aprepitant on the pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits.

Kura Raghunandan Reddy RR Kilari Eswar Kumar EK Shaik Mastan M

PeerJ 20180522

<h4>Background</h4>Concomitant drug administration is a general phenomenon in patients with chronic diseases such as diabetes mellitus. Among the currently available oral antidiabetic drugs, gliclazide is a commonly prescribed drug considering its multiple benefits in diabetic patients. Aprepitant is a commonly prescribed antiemetic drug which is mainly metabolized by CYP3A4, reported to have modest inductive and inhibitory effects on CYP2C9 and CYP3A4, respectively. Since gliclazide is metaboli ...[more]

PMID: 29844963

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Project description:Introduction:Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism. Objective:Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control. Methods:SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol®888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study. Results:The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron®). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.

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Influence of aprepitant on the pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits.

Publications

Influence of aprepitant on the pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits.

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