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OPEN ACCESSHuman & Veterinary MedicineInternational Journal of the Bioflux Society Research Article

Volume 8 | Issue 1 Page 59 HVM Bioflux

http://www.hvm.bioflux.com.ro/

Pharmacokinetic interaction between fluvoxamine and lansoprazole in healthy volunteers

1Maria A. Neag, 2Laurian Vlase, 1Anca D. Buzoianu, 1Corina I. Bocan, 3Petru A. Mircea, 2Sorin E. Leucua, 4Adina Popa, 2Dana Muntean1 Departement of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2 Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 3 Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 4 Department of Clinical Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

document/Prevacid_PM_-_25SEP08.pdf). Pharmacokinetics of repeated doses is similar to that of a single dose (Shi & Klotz 2008). Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 g/ml (http://www.abbott.ca/static/content/document/Prevacid_PM_-_25SEP08.pdf).The main enzyme involved in the metabolism of PPIs is CYP2C19. CYP3A4 is also involved in the PPI metabolism, but in a lesser extent (Ozdil et al 2010). Lansoprazole is extensively and rap-idly (t1/2: 12 h) metabolized into sulfone and 5-hydroxylated metabolites by CYP3A4 and CYP2C19 (Shi & Klotz 2008, Yacyshyn & Thomson 2002). Following single dose oral ad-ministration of lansoprazole, virtually no unchanged lansopra-zole was excreted in the urine. After a 30 mg single oral dose of lansoprazole, approximately one-third of the dose was ex-creted in the urine and approximately two-thirds were recov-ered in the feces. This implies a significant biliary excretion of the metabolites of lansoprazole (http://www.abbott.ca/static/content/document/Prevacid_PM_-_25SEP08.pdf).

Abstract. Background: Fluvoxamine is an inhibitor of the main metabolizing enzymes of lansoprazole and it could influence its pharmacoki-netics. The changes in lansoprazole pharmacokinetics could have clinical significance concerning safety of the therapy. Objective: The main objective of this study was to evaluate the pharmacokinetic interaction of fluvoxamine with lansoprazole in healthy volunteers. Methods: A dose of 30 mg lansoprazole, alone or in combination with 100 mg fluvoxamine was administered to 11 healthy male volunteers in a two treat-ments study design, separated by 6 days period in which the fluvoxamine alone was administrated as a single p.o. daily dose. Plasma concen-trations of lansoprazole were determined during a 12 hour period following drug administration using a validated LC/MS analytical method. Pharmacokinetic parameters of lansoprazole were calculated using non-compartmental analysis. Results: In the two periods of treatments, the mean peak plasma concentrations (Cmax) were 699.9 ng/ml (lansoprazole alone) and 1190 ng/ml (lansoprazole after pre-treatment with fluvox-amine). The observed areas under the curve (AUC0-t) were 1955 ng.hr/ml and 6467 ng.hr/ml whereas the total areas under the curve (AUC0-) were 2048 ng.hr/ml and 7813 ng.hr/ml, respectively. The Tmax (time to reach Cmax) were 2.35 hr and 3.55 hr. The elimination rate constants (Kel) were 0.54 hr-1 and 0.25 hr-1 for lansoprazole administered alone or after pre-treatment with fluvoxamine. The half-life values (t) were 1.43 hr and 3.51 hr, whereas the mean residence time 3.8 hr and 7.5 hr, respectively. Statistically significant differences were observed for Cmax (p=0.0001), AUC0-t (p

Neag et al 2016

Volume 8 | Issue 1 Page 60 HVM Bioflux

http://www.hvm.bioflux.com.ro/

Pharmacokinetic drug-drug interactions are common for medi-cation whose clearance involves CYP-mediated oxidative me-tabolism in the liver. Given the hepatic metabolism of the pro-ton-pump inhibitors (PPIs) and their effect on hepatic enzymes, one might anticipate a potential for clinically important drug interactions. The potential for omeprazole to interact with oth-er medications has been extensively studied. Lansoprazole has fewer documented drug interactions than omeprazole (Robinson & Horn 2003).Fluvoxamine is an antidepressant for oral administration that is effective through selective inhibition of serotonin reuptake, widely used for treatment of depression and other psychiatric disorders (Katoh et al 2010). After oral administration, fluvox-amine is almost completely absorbed from the gastrointestinal tract, and the extent of absorption is unaffected by the pres-ence of food (Ordacgi et al 2009); oral bioavailability in hu-mans is approximately 50% (Van Harten 1995); 80% is bound to plasma proteins (Klinger & Merlob 2008). Fluvoxamine is extensively metabolized in the liver (Orlando et al 2010) by oxidative demethylation and oxidative deamination (Hiemke & Hartter 2000). The half-life of fluvoxamine is approximately 1 day (Westenberg & Sandner 2006). Fluvoxamine is a potent CYP1A2 and CYP2C19 inhibitor, and a moderate CYP2C9, CYP2D6, and CYP3A4 inhibitor (Hemeryck & Belpaire 2002).Being inhibitor of the main metabolizing enzymes of lansopra-zole, fluvoxamine may influence its pharmacokinetics and it is important to determine whether a pharmacokinetic interaction occurs between these drugs, this being the aim of our study. Although it could have clinical significance concerning effica-cy and safety of the therapy, to the date this pharmacokinetic interaction was not reported.

Patients and methodsSubjectsEleven, non-smoking males, aged 22-29 years old took part in the study. The study was conducted according to the principles of Declaration of Helsinki (1964) and its amendments (Tokyo 1975, Venice 1983, Hong Kong 1989). The clinical protocol was reviewed and approved by the Ethics Committee of the University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania. As provided in the study protocol, a written informed consent in compliance with the current revision of the Declaration of Helsinki has been obtained from each sub-ject prior to enrolment, during which they are informed of their rights and obligations, potential side effects and other study de-tails. The volunteers were healthy according to history, physi-cal examination and laboratory tests, had no history of alcohol or drug abuse and did not take any regular medication. For the conclusion of the study, each subject underwent a final medical examination. Each subject was financially compensated for the participation to the study.

Study designThe study consisted of 2 periods: Period 1 (Reference), when each volunteer received a single dose of 30 mg lansoprazole and Period 2 (Test), when each volunteer received a single dose of 30 mg lansoprazole and 100 mg fluvoxamine. Between the two periods, the subjects were treated for 6 days with a single daily dose of 100 mg fluvoxamine. In other studies, steady-state

plasma concentrations were achieved within a week, after 100 mg fluvoxamine/day (Ordacgi et al 2009). All the drugs were administered in the morning, following an overnight fast.The pharmaceutical products used were LevantTM (enteric-coat-ed capsules containing 30 mg lansoprazole, producer Ranbaxy Ltd - UK) and Fevarin (capsules containing 100 mg fluvoxam-ine, producer Solvay Pharmaceuticals, Netherlands). During each study period venous blood (5 ml) was drawn into heparinized tubes before drug administration as well as at 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10 and 12 hours after drug administration and the separated plasma was stored frozen (-20 C) until analysis.

Analysis of plasma samples Lansoprazole plasma concentrations were determined by a vali-dated high throughput liquid chromatography-mass spectrometry method. The HPLC system was an Agilent 1100 series (binary pump, autosampler, thermostat) (Agilent Technologies, USA) and was coupled with an Brucker Ion Trap SL (Brucker Daltonics GmbH, Germany). A Zorbax SB-C18 chromatographic column (100 mm x 3.0 mm i.d., 3.5 m) (Agilent Technologies) was used. The mobile phase consisted of 40:60 (V/V) 2 mM ammonium acetate in water : methanol. The flow rate was 1 ml/min and the thermostat temperature set at 450C. The mass spectrometry detection was in multiple reactions monitoring mode (MRM), positive ions, using an electrospray ionization source. The ion transitions monitored were m/z 370m/z 252.1 ml methanol was added to 0.2 ml plasma in an Eppendorf tube. The tube was vortex-mixed for 10 seconds, and then centrifuged for 5 min at 10000 rpm. The supernatant was transferred to an autosampler vial and 1 l was injected into the LC/MS system.The calibration curve of lansoprazole was linear at a concen-tration range of 20-2000 ng/ml plasma, with a correlation co-efficient r= 0.994. At quantification limit, accuracy and preci-sion were 9.4% and 6.9% (intra-day) and 11.8% and 12.7% (inter-day), respectively.

Pharmacokinetic analysisNoncompartmental pharmacokinetic analysis was performed to determine the pharmacokinetic parameters of lansoprazole given alone or in combination with fluvoxamine. The maxi-mum plasma concentration (Cmax, ng/ml) and the time to reach the peak concentration (tmax, hr) were obtained directly by the visual inspection of each subjects plasma concentration-time profile. The area under the concentration-time curve from time zero to the last measurable concentration at time t (AUC0-t) was calculated using the trapezoidal rule. The area was extrapolated to infinity (AUC0-) by addition of Ct/Kel to AUC0-t where Ct is the last quantifiable drug concentration and Kel is the elimi-nation rate constant. Kel was estimated by the least-square re-gression of plasma concentration-time data points lying i

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