Application of high-performance liquid chromatography for the analysis and pharmocokinetics of mephenoxalone
- Authors: Van der Westhuizen, Fiona
- Date: 1988 , 2013-03-06
- Subjects: High performance liquid chromatography , Central nervous system depressants
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3810 , http://hdl.handle.net/10962/d1004385 , High performance liquid chromatography , Central nervous system depressants
- Description: Mephenoxalone is a mild central nervous system depressant with activity resembling that of meprobamate. Since its introduction in 1961 mephenoxalone has been used as an anxiolytic and as a muscle relaxant, although the latter effect is weak. Preliminary studies on the absorption and disposition of mephenoxalone have been conducted in beagle dogs but no pharmacokinetic data from human studies have been reported, except for a single study in which the biotransformation products present in human urine were identified. Methods presently available for the determination of mephenoxalone in biological fluids lack the sensitivity, specificity and precision required for detailed pharmacokinetic studies. In this study, a rapid, sensitive, precise reverse-phase high-performance liquid chromatographic method with ultraviolet detection at 200nm was employed for the determination of mephenoxalone in biological fluids. Serum and urine samples were prepared for chromatographic analysis using simple liquid-liquid extraction techniques. The application of the assay to pharmacokinetic studies in humans is presented. After administration of a single oral dose of 400mg mephenoxalone dispersed in 150ml water to six young, healthy volunteers, the compound was rapidly absorbed with the peak concentration of 8μg/ml occurring after about 1 hour. The elimination half-life was approximately 3 hours. The drug was extensively metabolized with only about 1 percent of the administered dose being excreted unchanged in the urine after 24 hours. The bioavailability of a newly developed mephenoxalone-containing tablet was also investigated. The drug was absorbed more rapidly from the tablet than from the dispersed dose. This was attributed to a shorter in vivo dissolution time on the basis of in vitro tests, but this effect is not expected to be clinically significant. In addition, two human urinary metabolites of mephenoxalone were identified as unconjugated hydroxylated derivatives using thermospray HPLC-mass spectrometry. The plasma protein-binding properties of mephenoxalone were also investigated.
- Full Text:
- Authors: Van der Westhuizen, Fiona
- Date: 1988 , 2013-03-06
- Subjects: High performance liquid chromatography , Central nervous system depressants
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3810 , http://hdl.handle.net/10962/d1004385 , High performance liquid chromatography , Central nervous system depressants
- Description: Mephenoxalone is a mild central nervous system depressant with activity resembling that of meprobamate. Since its introduction in 1961 mephenoxalone has been used as an anxiolytic and as a muscle relaxant, although the latter effect is weak. Preliminary studies on the absorption and disposition of mephenoxalone have been conducted in beagle dogs but no pharmacokinetic data from human studies have been reported, except for a single study in which the biotransformation products present in human urine were identified. Methods presently available for the determination of mephenoxalone in biological fluids lack the sensitivity, specificity and precision required for detailed pharmacokinetic studies. In this study, a rapid, sensitive, precise reverse-phase high-performance liquid chromatographic method with ultraviolet detection at 200nm was employed for the determination of mephenoxalone in biological fluids. Serum and urine samples were prepared for chromatographic analysis using simple liquid-liquid extraction techniques. The application of the assay to pharmacokinetic studies in humans is presented. After administration of a single oral dose of 400mg mephenoxalone dispersed in 150ml water to six young, healthy volunteers, the compound was rapidly absorbed with the peak concentration of 8μg/ml occurring after about 1 hour. The elimination half-life was approximately 3 hours. The drug was extensively metabolized with only about 1 percent of the administered dose being excreted unchanged in the urine after 24 hours. The bioavailability of a newly developed mephenoxalone-containing tablet was also investigated. The drug was absorbed more rapidly from the tablet than from the dispersed dose. This was attributed to a shorter in vivo dissolution time on the basis of in vitro tests, but this effect is not expected to be clinically significant. In addition, two human urinary metabolites of mephenoxalone were identified as unconjugated hydroxylated derivatives using thermospray HPLC-mass spectrometry. The plasma protein-binding properties of mephenoxalone were also investigated.
- Full Text:
Phenylpropanolamine : analytical and pharmacokinetic studies using high-performance liquid chromatography
- Authors: Scherzinger, Sabine Hilda
- Date: 1988
- Subjects: Phenylpropanolamine , Pharmacokinetics , High performance liquid chromatography
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: vital:3811 , http://hdl.handle.net/10962/d1004528
- Description: Phenylpropanolamine (PPA), a synthetic sympathomimetic amine structurally related to ephedrine has been widely used over t he past 40 years as a nasal decongestant and appetite suppressant. It has been the focus of much controversy concerning the efficacy of the drug in its use as an anorectic agent, and due to the side effects caused by the higher doses of PPA required for appetite suppression. Although extensively used, there is little information concerning the determination of PPA in biological fluids and on the pharmacokinetics of this drug. An adaptation of a published high-performance liquid chromatographic (HPLC) assay for PPA in serum and urine using U.V. detection at 210 nm is presented. PPA was separated in the reversed phase mode. The method has a limit of sensitivity of 5.0 ng/mL and 10.0 ng/mL in serum and urine respectively. Serum concentration data following a single 25 mg dose of phenylpropanolamine in human volunteers demonstrate the application of the analytical method for bioavailability and pharmacokinetic studies. After the administration of 25 mg, 50 mg or 100 mg PPA.HCl solutions to 5 human volunteers, a dose proportionality study demonstrated that PPA appears to exhibit linear kinetics. Linear one body compartment kinetics were assumed and the wagner-Nelson method used to transform in vivo serum data to absorption plots. The serum data were fitted to a model using nonlinear regression techniques to characterize the pharmacokinetic processes of PPA. The absorption of phenylpropanolamine appears to be discontinuous and the drug seems to favour a two body compartment model. The pharmacokinetic parameters obtained from a steady state study using multiple dosing of PPA.HCl solutions compared with those found from previous studies after the administration of sustained-release formulations. A plasma protein binding study using equilibrium dialysis demonstrated that PPA is not highly protein bound in the blood.
- Full Text:
- Authors: Scherzinger, Sabine Hilda
- Date: 1988
- Subjects: Phenylpropanolamine , Pharmacokinetics , High performance liquid chromatography
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: vital:3811 , http://hdl.handle.net/10962/d1004528
- Description: Phenylpropanolamine (PPA), a synthetic sympathomimetic amine structurally related to ephedrine has been widely used over t he past 40 years as a nasal decongestant and appetite suppressant. It has been the focus of much controversy concerning the efficacy of the drug in its use as an anorectic agent, and due to the side effects caused by the higher doses of PPA required for appetite suppression. Although extensively used, there is little information concerning the determination of PPA in biological fluids and on the pharmacokinetics of this drug. An adaptation of a published high-performance liquid chromatographic (HPLC) assay for PPA in serum and urine using U.V. detection at 210 nm is presented. PPA was separated in the reversed phase mode. The method has a limit of sensitivity of 5.0 ng/mL and 10.0 ng/mL in serum and urine respectively. Serum concentration data following a single 25 mg dose of phenylpropanolamine in human volunteers demonstrate the application of the analytical method for bioavailability and pharmacokinetic studies. After the administration of 25 mg, 50 mg or 100 mg PPA.HCl solutions to 5 human volunteers, a dose proportionality study demonstrated that PPA appears to exhibit linear kinetics. Linear one body compartment kinetics were assumed and the wagner-Nelson method used to transform in vivo serum data to absorption plots. The serum data were fitted to a model using nonlinear regression techniques to characterize the pharmacokinetic processes of PPA. The absorption of phenylpropanolamine appears to be discontinuous and the drug seems to favour a two body compartment model. The pharmacokinetic parameters obtained from a steady state study using multiple dosing of PPA.HCl solutions compared with those found from previous studies after the administration of sustained-release formulations. A plasma protein binding study using equilibrium dialysis demonstrated that PPA is not highly protein bound in the blood.
- Full Text:
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