Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Larkin, John G.; Mckee, P. J. W.; Forrest, Gerard; Beastall, G. H.; Park, B. K.; Lowrie, J. I.; Lloyd, Peter; Brodie, MJ

doi:10.1111/j.1365-2125.1991.tb03858.x

Cited by 114 publications

(44 citation statements)

References 31 publications

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“…The marked reduction in plasma EE and LN is in contrast to the reported inability of OCBZ to affect the CYP3A-mediated production of 6-j3-hydroxycortisol (lo), its absent or minor effect on antipyrine clearance (10,18), and its modest influence on the kinetics of another CYP3A substrate, felodipine ( 1 9). This apparent discrepancy might be explained by differences in dosages (a 600-mg OCBZ dose was tested in the 6-phydroxycortisol study) or by the heterogeneous nature of CYP3A isoenzymes.…”

Section: Discussionmentioning

confidence: 81%

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Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

et al. 1999

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ICWCNS, Basel, and if1.P.A.S. SA, Stubio, Switzerland Summary: Purpose: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives.Methods: Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mglday) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 p,g ethinylestradiol (EE) and 250 tJ-g levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle.Results: Compared with placebo, areas under the plasma concentration curves (AUC,,,,, geometric means) decreased by 47% for both EE (from 1,677 to 886 pgWml; p < 0.01) and LN(from 137 to 73 ngWml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < O.Ol), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p i 0.01).Conclusions: OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.

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Section: Discussionmentioning

confidence: 81%

“…Blood samples (14 ml) for the determination of plasma EE and LN concentrations were collected just before the last dose of the oral contraceptive (day 2 1, time 0) and 1, 2, 3, 4, 6, 8, 10,12,24,32, and 48 h thereafter. Serum progesterone levels, as indicator of possible ovulation, also were determined in the sample at time 0.…”

Section: Methodsmentioning

confidence: 99%

Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

et al. 1999

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“…11 However, it has a different metabolic pathway in the liver; instead of by oxidation, it is mainly metabolized by reduction, and does not appear to induce the oxidative P450-enzyme system to the same extent as CBZ. 12 Previous studies have shown that the CBZ-induced changes in endocrine and metabolic function equilibrate after CBZ is replaced with OXC. 13,14 Thus, OXC has been suggested to be a safe AED with regard to endocrine and metabolic effects.…”

Section: Neurology 2001;56:31-36mentioning

confidence: 99%

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

Rättyä¹,

Turkka²,

Pakarinen³

et al. 2001

Neurology

176

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Article abstract-Background: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. Methods: Reproductive endocrine function was evaluated in 90 men taking VPA (n ϭ 21), CBZ (n ϭ 40), or OXC (n ϭ 29) as monotherapy for epilepsy and in 25 healthy control men. Results: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormonebinding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (Ͻ900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose Ն900 mg. Conclusions: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not. NEUROLOGY 2001;56:31-36 Reproductive endocrine disorders and sexual dysfunction have frequently been attributed to epilepsy itself, but antiepileptic drugs (AED) also have various effects on endocrine function.1-7 Valproate (VPA) has been implicated to have only minor effects on the hormonal system in men with epilepsy.3,4 However, there is growing evidence that VPA therapy induces endocrine disorders in women with epilepsy, which are characterized by hyperandrogenism and hyperinsulinemia that are related to obesity. 5,6 Carbamazepine (CBZ) is one of the most widely used first-line AED. The use of CBZ is associated with a progressive increase in circulating levels of sex hormone-binding globulin (SHBG) and, consequently, in a decreased proportion of free, bioactive testosterone, which may result in sexual dysfunction in some men with epilepsy after long-term CBZ treatment.8 CBZ-related endocrine changes have been attributed to the induction of the hepatic P450-enzyme system by the drug. 9,10Oxcarbazepine (OXC), a keto-derivative of CBZ, is a new AED that closely resembles CBZ in structure.11 However, it has a different metabolic pathway in the liver; instead of by oxidation, it is mainly metabolized by reduction, and does not appear to induce the oxidative P450-enzyme system to the same extent as CBZ.12 Previous studies have shown that the CBZ-induced changes in endocrine and metabolic function equilibrate after CBZ is replaced with OXC.13,14 Thus, OXC has been suggested to be a safe AED with regard to endocrine and metabolic effects. However, there is evidence that OXC may also induce liver enzymes when prescribed at higher doses. 15 Endocrine effects of OXC have not been previously assessed...

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“…Oxcarbazepine is rapidly and completely absorbed and metabolized to its monohydroxy derivative 10-hydroxycarbazepine (Larkin et al, 1991;Lloyd et al, 1994;May et al, 2003). 10-Hydroxycarbazepine is further metabolized, primarily by glucuronidation.…”

Section: Oxcarbazepinementioning

confidence: 99%

Therapeutic Drug Monitoring of Antiepileptic Medications

Krasowski¹

2011

Novel Treatment of Epilepsy

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Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Cited by 114 publications

References 31 publications

Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

Therapeutic Drug Monitoring of Antiepileptic Medications

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