Pharmacokinetic study of orphenadrine using high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS)

Lee, Soo-Youn; Sohn, Jong–Ryeul; Kim, Jong Won; Kim, Yoon Gyoon; Moon, Chul Jin; Lee, Eun Hee

doi:10.1016/j.jchromb.2006.02.056

Cited by 17 publications

(5 citation statements)

References 6 publications

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“…On the other hand, blood concentrations of orphenadrine greater than 0.5 µg/mL (~0.2 µM) may cause toxic reactions [28]. Such toxic effects are frequently observed because orphenadrine is widely available and the drug can be deliberately abused for its analgesic, stimulating, and euphoriant effects, as well as for suicide purpose [18,38].…”

Section: Discussionmentioning

confidence: 99%

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine

Desaphy

Dipalma

Bellis

et al. 2009

Pain

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Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.

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Section: Discussionmentioning

confidence: 99%

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine

Desaphy

Dipalma

Bellis

et al. 2009

Pain

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“…The recommended method for determination of orphenadrine in USP [4] is HPLC while the British Pharmacopoeia (BP) recommends a potentiometric titration procedure for its assay of the raw material [25]. Several methods for determination of Orphenadrine in pharmaceutical formulations have been described, via spectrophotometry [26-30], GC [31], capillary electrophoresis [32-35], TLC [36] and HPLC [37-39]. …”

Section: Introductionmentioning

confidence: 99%

Spectrophotometric determination of tizanidine and orphenadrine via ion pair complex formation using eosin Y

Walash

Belal

Eid

et al. 2011

Chemistry Central Journal

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A simple, sensitive and rapid spectrophotometric method was developed and validated for the determination of two skeletal muscle relaxants namely, tizanidine hydrochloride (I) and orphenadrine citrate (II) in pharmaceutical formulations. The proposed method is based on the formation of a binary complex between the studied drugs and eosin Y in aqueous buffered medium (pH 3.5). Under the optimum conditions, the binary complex showed absorption maxima at 545 nm for tizanidine and 542 nm for orphenadrine. The calibration plots were rectilinear over concentration range of 0.5-8 μg/mL and 1-12 μg/mL with limits of detection of 0.1 μg/mL and 0.3 μg/mL for tizanidine and orphenadrine respectively. The different experimental parameters affecting the development and stability of the complex were studied and optimized. The method was successfully applied for determination of the studied drugs in their dosage forms; and to the content uniformity test of tizanidine in tablets.

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“…Plasma levels of orphenadrine and paracetamol were analyzed using liquidchromatography-tandem mass spectrometer (LCMSMS). The current assay method was developed based on the LC-MS/MS method by Lee et al [19]. The LC system comprised an Agilent 1200 Series binary pump (Agilent, Waldbronn, Germany), an Agilent 1200 Series degasser (Agilent, Waldbronn, Germany), an Agilent 1200 Series thermostated column compartment (Agilent, Waldbronn, Germany) and an Agilent 1200 Series instant pilot (Agilent, Waldbronn, Germany).…”

Section: Sample Analysismentioning

confidence: 99%

A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition

Cheah

Mah

Pang

et al. 2020

BMC Pharmacol Toxicol

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Background: Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/ orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia. Method: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (− 15°C to − 25°C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatographytandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC 0-∞ , AUC 0-t and C max were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC 0-∞ , AUC 0-t and C max ratio must be within the range of 80.00-125.00%.

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Pharmacokinetic study of orphenadrine using high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS)

Cited by 17 publications

References 6 publications

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine

Spectrophotometric determination of tizanidine and orphenadrine via ion pair complex formation using eosin Y

A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition

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