Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: In vitro and in vivo comparison and calculation of in vivo inhibition constants*

Tran, A.; Rey, Elisabeth; Pons, Gérard; Rousseau, Marina; d’Athis, Philippe; Olivé, G; Mather, Gary G.; Bishop, Frances E.; Wurden, Colleen J.; Labroo, Rita; Trager, William; Kunze, Kent L.; Thummel, Kenneth E.; Vincent, J.; Gillardin, Jean-Pierre; Lepage, F.; Levy, René H.

doi:10.1016/s0009-9236(97)90044-8

Cited by 88 publications

(64 citation statements)

References 42 publications

(3 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similarly, the hepatic uptake of many lipophilic compounds is not necessarily restricted by protein binding (Kurz and Fichtl, 1983;Pacifici and Viani, 1992), and it has been found that the antifungal activity of itraconazole and ketoconazole is not diminished despite extensive binding albumin (Schäfer-Korting et al, 1995). In agreement, Tran et al (1997) have reported that the K i value of stiripentol obtained in microsomal studies is more consistent with total plasma concentration than unbound concentration. All these reports suggest that factors, other than protein binding, may be involved in a given biological process.…”

mentioning

confidence: 67%

Effect of Albumin on Phenytoin and Tolbutamide Metabolism in Human Liver Microsomes: An Impact More Than Protein Binding

Tang

Lin²,

Rodrigues³

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The cytochrome P450 (P450)-dependent conversion of phenytoin (PHT) to p-hydroxy phenytoin (pHPPH), and tolbutamide (TLB) to 4-hydroxy tolbutamide (hydroxy-TLB), in human liver microsomes was studied in the presence of increasing concentrations (0-4%) of bovine serum albumin (BSA). Therefore, the free fraction (f u ) of PHT and TLB varied. Whereas the f u of PHT (5 M) decreased, an increase (3-fold), rather than a decrease in the pHPPH formation rate was observed when BSA (<1%) was present. The stimulation was attributed to a significant decrease in apparent K m . The change, however, was diminished as the BSA concentration reached 4% (PHT f u ‫؍‬ 0.2), in which the reaction velocity remained the same as that measured in the absence of BSA. Therefore, unchanged K m (16.2 ؎ 0.7 M) and V max (9.4 ؎ 0.2 pmol/min/mg of protein) values were determined based on total PHT concentrations, whereas correction for f u led to an unbound K m (K mu ) of ϳ3.2 M. Similarly, the metabolism of TLB (50 M) was enhanced (ϳ2-fold) in the presence of 0.25% BSA but remained only 35% of the control activity (no BSA) at 1% BSA. However, the remaining activity was higher (3-fold) than that determined with an equivalent free concentration of TLB (4 M) calculated according to its f u (0.08). The difference became less significant when BSA concentration was 4% (f u < 0.02). Collectively, the results suggest a 2-fold effect of BSA on PHT and TLB hydroxylation: first, facilitation of the reactions via a decrease in K m ; second, a decrease in f u leading to a drop in reaction rate. For a given P450 reaction, therefore, the effect of BSA may depend upon enzyme affinity, catalytic capacity, and the extent of protein binding.For the longest time, it has been accepted that only unbound drug contributes to pharmacological activities. This free drug hypothesis has also found applications in drug transport, drug metabolism and disposition, receptor binding, enzyme kinetics, and inhibition processes. However, some recent findings appear to contradict this hypothesis. For example, it has been noted that during one passage through the brain, in many cases, more drug than "free drug" can penetrate through the blood-brain barrier (Spector, 2000). Similarly, the hepatic uptake of many lipophilic compounds is not necessarily restricted by protein binding (Kurz and Fichtl, 1983;Pacifici and Viani, 1992), and it has been found that the antifungal activity of itraconazole and ketoconazole is not diminished despite extensive binding albumin (Schäfer-Korting et al., 1995). In agreement, Tran et al. (1997) have reported that the K i value of stiripentol obtained in microsomal studies is more consistent with total plasma concentration than unbound concentration. All these reports suggest that factors, other than protein binding, may be involved in a given biological process.Recently, with the growing demand for quantitative predictions of in vivo pharmacokinetics and drug-drug interactions, this free drug hypothesis has been investigated. For instance, it ...

show abstract

mentioning

confidence: 67%

Effect of Albumin on Phenytoin and Tolbutamide Metabolism in Human Liver Microsomes: An Impact More Than Protein Binding

Tang

Lin²,

Rodrigues³

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…The approach used to calculate K i iv is based on the competitive inhibition model used previously (Adedoyin et al, 1987;Shaw and Houston, 1987;Kunze and Trager, 1996;Tran et al, 1997;Yao et al, 2001). The model includes the following assumptions: 1) product formation is described by Michaelis-Menten kinetics with competitive inhibition; 2) concentrations of (S)-mephenytoin are much lower than its K M ; 3) only one enzyme mediates the formation of 4-OH-meph; 4) after oral administration, the operating clearance of (S)-mephenytoin is its intrinsic clearance because (S)-mephenytoin has a relatively large clearance (Ito et al, 1998); and 5) fluvoxamine does not affect the elimination of 4-OH-meph.…”

Section: Calculation Of K I Iv Values For Cyp2c19mentioning

confidence: 99%

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

Yao¹,

Kunze²,

Trager³

et al. 2003

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…[16] STP mikrozomal sitokrom izoenzimlerinden CYP3A4, CYP1A2, CYP2C19'u inhibe eder. [17] STP birçok ilaçla etkileşime girer. STP'nin metabolizması enzim indükleyen AEİ'ler tarafından arttırılırken STP diğer AEİ'lerin metabolizmasını güçlü bir şekilde inhibe eder.…”

Section: Discussionunclassified

A Case of Dravet Syndrome Who Developed Acute Reversible Encephalopathy That May Have Been Caused by Hyperamonnemia Due to Pharmacokinetic Interaction Between Valproate and Stiripentol

Atmaca¹,

Gürses²,

Marufoglu³

et al. 2012

Epilepsi

View full text Add to dashboard Cite

ÖzetStiripentol (STP), Dravet sendromunda valproat (VPA) ve klobazama ek olarak kullanılmak üzere onay almış yeni bir antiepileptik ilaç (AEİ)'dir. Diğer taraftan özellikle tedaviye dirençli epilepsilerde sık görülen ani beklenmedik ölüm ("sudden unexpected death in epilepsy" SUDEP) riski Dravet sendromunda da yüksektir. Kullanmakta olduğu çeşitli AEİ'lere karşın nöbetleri devam etmekte olan, birkaç kez status epileptikus (SE) veya yapılan intravenöz diazepam sonrası 'kardiyopulmoner arest'ten geçmiş olan olgumuzda da tedaviye STP eklenmiş, tedaviye başlandıktan altı ay sonra akut geçici ensefalopati tablosu oluşmuştur. Bu tabloya STP'nin VPA ile etkileşimi sonucu ortaya çıkan hiperamonyeminin neden olabileceği üzerinde durulmuştur. Dravet sendromu, SUDEP ve STP hakkında son literatür eşliğinde tedavi seçe-nekleri ve koruyucu önlemler tartışılmıştır.Anahtar sözcükler: Dravet sendromu; hiperamonyemi; stiripentol; SUDEP; valproat. SummaryStiripentol (STP), a recent antiepileptic drug, has been approved for use in addition to valproat (VPA) and clobazam in Dravet syndrome.On the other hand, the incidence of sudden unexpected death in epilepsy (SUDEP) commonly seen in patients with intractable epilepsy, is high in patients with Dravet yndrome. In our case, who was resistant to polytherapy and had multiple cardiopulmonary arrest due to status epilepticus (SE) or intravenous diazepam; STP was used in combination with other antiepileptic drugs (AED). However, acute reversible encephalopathy developed after six months of therapy. It is argued that the condition may have been caused by hyperamonnemia due to pharmacokinetic interaction between VPA and STP. Treatment options and protective measures are discussed using recent literature on Dravet syndrome, SUDEP and STP.

show abstract

Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: In vitro and in vivo comparison and calculation of in vivo inhibition constants*

Abstract: Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.

Cited by 88 publications

References 42 publications

Effect of Albumin on Phenytoin and Tolbutamide Metabolism in Human Liver Microsomes: An Impact More Than Protein Binding

Effect of Albumin on Phenytoin and Tolbutamide Metabolism in Human Liver Microsomes: An Impact More Than Protein Binding

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

A Case of Dravet Syndrome Who Developed Acute Reversible Encephalopathy That May Have Been Caused by Hyperamonnemia Due to Pharmacokinetic Interaction Between Valproate and Stiripentol

Contact Info

Product

Resources

About