Effects of Menthol on the Pharmacokinetics of Triazolam and Phenytoin

Hoshino, Motohiro; Ikarashi, Nobutomo; Hirobe, Ryuta; Hayashi, Momoko; Hiraoka, Hironori; Yokobori, Kohsuke; Ochiai, Takumi; Kusunoki, Yoshiki; Kon, Risako; Tajima, Masataka; Ochiai, Wataru; Sugiyama, Kiyoshi

doi:10.1248/bpb.b14-00764

Cited by 5 publications

(2 citation statements)

References 24 publications

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“…Drug doses were selected based on previous reports relevant to phenytoin, 17,18) gabapentin, 19,20) and levetiracetam. 21) Each drug was administered orally at a volume of 0.1 mL/100 g body weight once per day for 12 weeks.…”

Section: Methodsmentioning

confidence: 99%

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats

Kanda

Izumo

Kobayashi

et al. 2017

Biological & Pharmaceutical Bulletin

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Long-term treatment with antiepileptic drugs (AEDs) is accompanied by reduced bone mass that is associated with an increased risk of bone fractures. Although phenytoin has been reported to adversely influence bone metabolism, little is known pertaining to more recent AEDs. The aim of this study was to evaluate the effects of gabapentin or levetiracetam on bone strength, bone mass, and bone turnover in rats. Male Sprague-Dawley rats were orally administered phenytoin (20 mg/kg), gabapentin (30 or 150 mg/kg), or levetiracetam (50 or 200 mg/kg) daily for 12 weeks. Bone histomorphometric analysis of the tibia was performed and femoral bone strength was evaluated using a three-point bending method. Bone mineral density (BMD) of the femur and tibia was measured using quantitative computed tomography. Administration of phenytoin significantly decreased bone strength and BMD, which was associated with enhanced bone resorption. In contrast, treatment with gabapentin (150 mg/kg) significantly decreased bone volume and increased trabecular separation, as shown by bone histomorphometric analysis. Moreover, the bone formation parameters, osteoid volume and mineralizing surface, decreased after gabapentin treatment, whereas the bone resorption parameters, osteoclast surface and number, increased. Levetiracetam treatment did not affect bone strength, bone mass, and bone turnover. Our data suggested that gabapentin induced the rarefaction of cancellous bone, which was associated with decreased bone formation and enhanced bone resorption, and may affect bone strength and BMD after chronic exposure. To prevent the risk of bone fractures, patients prescribed a longterm administration of gabapentin should be regularly monitored for changes in bone mass.Key words gabapentin; levetiracetam; osteoblast; osteoclast; rat Epilepsy is a chronic neurological disorder characterized by recurrent seizures. 1) Pharmacotherapy with antiepileptic drugs (AEDs) is the mainstay of treatment for epilepsy and is effective in the prevention of seizures. Patients with epilepsy usually require long-term treatment with AEDs; thus, the prevention of side effects is important in the continuation of medication.The bone is a metabolically active organ that undergoes continuous remodeling from bone resorption by osteoclasts and bone formation by osteoblasts.2) Under healthy conditions, the balance between bone formation and bone resorption is always uniform; thus, bone strength and bone mass are maintained. Certain pathological states and drugs affect normal bone remodeling, which can induce skeletal disorders, such as osteopenia or osteoporosis.3) A serious side effect associated with long-term administration of AEDs is the elevated risk of bone fracture owing to a decrease in bone mass.4-7) Patients taking AEDs are approximately 2-6 times more at risk of bone fracture than healthy individuals are. 8,9) Previous studies have demonstrated that treatment with phenytoin decreased bone mineral density (BMD) owing to enhanced bone resorption.10,11) Currently, new...

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Section: Methodsmentioning

confidence: 99%

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats

Kanda

Izumo

Kobayashi

et al. 2017

Biological & Pharmaceutical Bulletin

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“…The extraction of phenytoin in plasma and analysis using high-performance liquid chromatography-ultra violet (HPLC-UV) were performed as described previously. 15,16…”

Section: Methodsmentioning

confidence: 99%

Changes in the Pharmacokinetics of Phenytoin in Dextran Sulfate Sodium–Induced Ulcerative Colitis in Mice

et al. 2017

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We previously demonstrated that the expression levels of drug-metabolizing enzymes, cytochrome P450 (CYP) enzymes, in the liver are significantly decreased in a murine model of ulcerative colitis (UC). In this study, we investigated changes in the pharmacokinetics of phenytoin, a CYP2C substrate drug, in the presence of UC. Colitis was induced by feeding male mice 3.5% dextran sulfate sodium (DSS) dissolved in drinking water for 10 days. The messenger RNA (mRNA) expression of CYP2C29 and CYP2C37 and the protein expression of CYP2C in the liver were evaluated via real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. In DSS-treated animals, both mRNA and protein expression levels of CYP2C in the liver were significantly reduced relative to those in control animals (by 20%-40%). Phenytoin (30 mg/kg) was administered orally in a single dose to mice, and plasma concentrations were measured. Plasma concentrations of phenytoin were higher in the DSS-treated group than in the control group at 12, 24, and 36 hours after administration. Animals given DSS also exhibited a higher area under the plasma concentration-time curve extrapolated to infinity (AUC, 315 μg·h/mL), a delayed elimination half-life ( T, 8.1 hours), and a decreased body clearance (CL/F, 3.52 mL/h) compared with that of control animals (AUC, 215 μg·h/mL; T, 3.6 h; CL/F, 5.58 mL/h). This study indicated that the presence of UC decreases CYP2C expression levels in the liver, thereby delaying the metabolism of CYP2C substrates, including phenytoin, and increasing blood concentrations of these substrates.

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High-dose green tea polyphenol intake decreases CYP3A expression in a liver-specific manner with increases in blood substrate drug concentrations

Ikarashi

Ogawa

Hirobe

et al. 2016

European Journal of Pharmaceutical Sciences

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Effects of Menthol on the Pharmacokinetics of Triazolam and Phenytoin

Cited by 5 publications

References 24 publications

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats

Changes in the Pharmacokinetics of Phenytoin in Dextran Sulfate Sodium–Induced Ulcerative Colitis in Mice

High-dose green tea polyphenol intake decreases CYP3A expression in a liver-specific manner with increases in blood substrate drug concentrations

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