Inhibition of diazepam metabolism by fluvoxamine: A pharmacokinetic study in normal volunteers

Perucca, Emilio; Gatti, G.; Cipolla, Giovanna; Spina, Edoardo; Barel, Shimon; Soback, S.; Gips, M.; Bialer, Meir

doi:10.1038/clpt.1994.167

Cited by 86 publications

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“…These suggested that there is a large inter-individual difference in bioavailability of fluvoxamine. Many previous papers described the effect of fluvoxamine on the pharmacokinetics of other drugs, which were metabolized by CYP2C19, 8 CYP3A4, [26][27][28] and CYP1A2. 28,29 However, the specific isoenzymes involved in fluvoxamine metabolism have not been identified; nevertheless, in vitro and in vivo the drug potently inhibits the metabolism of substrates for CYP1A2.…”

Section: Discussionmentioning

confidence: 99%

“…3 Increases in fluvoxamine plasma concentrations have been reported when it is prescribed in combination with clomipramine 5 and butyrophenone. 6 Several reports indicate that fluvoxamine increases the plasma concentration of concurrently administered tricyclic antidepressants, 7 benzodiazepines, 8 carbamazepine 9 and theophilline. 10 This suggests the possibility that other drugs may be involved in drug interactions when co-administered with fluvoxamine in clinical drug therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

et al. 2003

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IntroductionFluvoxamine, 5-methyl-4′-trifluoromethylvalerophenone(E)-O-2-aminoethyloxime monomaleate, is one of several antidepressant agents known as selective serotonin reuptake inhibitors (SSRIS). The efficacy of fluvoxamine in depression has been reviewed in previous papers. 1,2 The clinical pharmacokinetics of fluvoxamine were also described in a previous paper. 3 Negligible amounts of fluvoxamine are excreted unchanged in the human urine. Urinary fluvoxamine metabolites have been identified as consisting of at least 9 different compounds. About 65% of these metabolites resulted from oxidative demethylation of the aliphatic methoxyl group, and 15% of metabolites are formed by degradation at the primary amino group. Fluvoxamino acid is the main primary metabolite in humans. 4 Therefore, the monitoring of fluvoxamino acid on the drug interaction study of fluvoxamine will be able to detect slight changes of fluvoxamine metabolism by co-administered drug in healthy volunteers and/or patients.The pharmacokinetics of fluvoxamino acid in human has not yet been studied sufficiently.Methods for the fluvoxamine by GC-MS, 12 HPLC with liquidliquid extraction of plasma samples [13][14][15][16][17] and HPLC with solidphase in-line extraction 18,19 were described in previous papers. The liquid-liquid extraction methods are not completely satisfactory because they are time-consuming and require a tedious procedure. We have reported a simple extraction method of several drugs and their metabolites by using a solid phase extraction cartridge. [20][21][22][23] However, an off-line solid phase extraction method for fluvoxamine has not been reported in previous papers. There is also no report for simultaneous determination of fluvoxamine and fluvoxamino acid in human plasma by HPLC.The extraction of fluvoxamine and fluvoxamino acid in human plasma using a solid phase method has some problems: one is the simultaneous extraction from a complex mixture of both acidic and basic compounds. Therefore, a specific extraction method and an efficient chromatographic system without interfering peaks was needed A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of fluvoxamine and its major metabolite fluvoxamino acid in plasma. Fluvoxamine and fluvoxamino acid in plasma were extracted using a C18 bonded-solid phase cartridge, followed by C4 reversed-phase HPLC separation. Fluvoxamine, fluvoxamino acid and moperone as an internal standard were detected by ultraviolet absorbance at 254 nm. It was possible to determine both fluvoxamine and fluvoxamino acid in the concentration range of 25.0 -200.0 ng/mL, respectively. The detection limits of both fluvoxamine and fluvoxamino acid were 10.0 ng/mL, respectively. The mean recoveries of fluvoxamine and fluvoxamino acid added to plasma were more than 94.0% and 96.5%, with a coefficient of variation of less than 7.6% and 8.2%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (C...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

et al. 2003

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“…Omeprazole, inhibitor of CYP2C19, decreased the clearance of intravenous diazepam by 27% (Andersson et al, 1990), and fluvoxamine, an inhibitor of CYP1A2, CYP2C19, and CYP3A4, reduced the apparent oral clearance of diazepam by 65%, and the elimination half-life was increased from 51 to 118 h (Perucca et al, 1994). It is noteworthy that ciprofloxacin, an inhibitor of CYP1A2, and cimetidine, an inhibitor of CYP1A2 and CYP3A4, reduced diazepam clearance by 37 and 38%, respectively (Kamali et al, 1993), but the exact mechanism for this is unknown.…”

Section: Cytochrome P450-mediated Drug Interactions and Benzodiazepinesmentioning

confidence: 99%

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

et al. 2011

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“…A suitable candidate enzyme was sought to test the hypothesis that RK i values will be conserved for a single inhibitor among the family of P450 1 enzymes. There is some in vivo evidence that fluvoxamine also inhibits the clearance of a number of drugs metabolized by CYP2C19, such as mephenytoin, chloroguanide, and diazepam (Perucca et al, 1994a;Xu et al, 1996;Jeppesen et al, 1997). In the case of the fluvoxaminemephenytoin interaction, the 0-to 8-h urine S/R ratio of mephenytoin increased from 0.16 to 0.55 after 100 mg/day fluvoxamine treatment for 2 weeks (Xu et al, 1996).…”

mentioning

confidence: 99%

“…Fluvoxamine also inhibited the CYP2C19 catalyzed bioactivation of chloroguanide: the formation clearance of 4-chlorophenylbiguanide decreased from 97 to 11 ml/min in CYP2C19-extensive metabolizers treated with 100 mg/day fluvoxamine for 6 days (Jeppesen et al, 1997). Diazepam oral clearance decreased from 0.4 to 0.14 ml/min/kg after treatment with 100 to 150 mg/day fluvoxamine for 4 days (Perucca et al, 1994a). The extent of inhibition observed in vivo is underpredicted with the reported in vitro K i values of fluvoxamine toward CYP2C19 (0.087-0.69 M; Rasmussen et al, 1998;Olesen and Linnet, 2000), when they are used in conjunction with the unbound plasma concentration of fluvoxamine.…”

mentioning

confidence: 99%

Comparison of In Vitro and In Vivo Inhibition Potencies of Fluvoxamine toward CYP2C19

Yao¹,

Kunze²,

Trager³

et al. 2003

Drug Metab Dispos

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ABSTRACT:A previous study suggested that fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (K i ) values of fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (S)-mephenytoin as a CYP2C19 probe. K i values based on total added fluvoxamine concentration (K i,total ) and unbound fluvoxamine concentration (K i,ub ) were calculated, and interindividual variability in K i values was examined in six nonfatty livers. There has been a growing interest in predicting in vivo metabolic drug-drug interactions from in vitro systems. In the case of inhibitionbased interactions, there is no consensus on the methodology for accurate predictions of the extent of in vivo inhibition based on in vitro data (Schmider et al., 1999;Yamano et al., 1999;Kohl and Steinkellner, 2000;Komatsu et al., 2000;Yao and Levy, 2002). Several issues remain unsolved, such as estimations of inhibition constants in vitro and inhibitor concentration around the enzyme site in vivo. For example, studies on fluvoxamine inhibition of CYP1A2 have shown that in vitro K i values varied with microsomal protein concentration (Yao et al., 2001), suggesting that the concentration of microsomal protein present in the incubation is a factor contributing to the variance in in vitro K i . However, even after correction for nonspecific binding of fluvoxamine in microsomes, there was still a 10-fold difference between the in vitro inhibition constant and the corresponding in vivo inhibition constant based on unbound fluvoxamine concentration in plasma.The 10-fold underprediction of fluvoxamine inhibition potency toward CYP1A2 activity in vivo, based on in vitro data, may be due to a number of factors. These include, but are not limited to, active uptake of fluvoxamine from plasma into hepatocytes, thereby increasing the amount of inhibitor available to the enzyme (partitioning), the presence of inhibitory metabolites of fluvoxamine in plasma, and/or environmental differences that may differentially affect enzyme behavior or affinity in the two systems. Should it be the case that some type of partitioning alone is the dominant factor governing the in vitro-in vivo difference, one might expect that the RK i (the ratio of the in vitro K i to the in vivo K i based on unbound concentration) of any enzyme inhibited by fluvoxamine would be similar to that of CYP1A2. In essence, RK i would be largely enzyme independent. However, if inhibitory metabolites or enzyme environment play important roles in promoting the RK i difference, RK i values might become enzyme-dependent. A suitable candidate enzyme was sought to test the hypothesis that RK i values will be conserved for a single inhibitor among the family of P450 1 enzymes. There is some in vivo evide...

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Inhibition of diazepam metabolism by fluvoxamine: A pharmacokinetic study in normal volunteers

Cited by 86 publications

References 0 publications

High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

Comparison of In Vitro and In Vivo Inhibition Potencies of Fluvoxamine toward CYP2C19

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