High-performance liquid chromatographic method for the simultaneous determination of nalbuphine and its prodrug, sebacoyl dinalbuphine ester, in dog plasma and application to pharmacokinetic studies in dogs

Pao, Li-Heng; Hsiong, Cheng-Huei; Hu, Oliver Yoa Pu; Ho, Shung‐Tai

doi:10.1016/s0378-4347(00)00326-1

Cited by 23 publications

(23 citation statements)

References 15 publications

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“…Nalbuphine was the only measurable metabolic product of SDN in the blood, as judged by the almost complete recovery of nalbuphine (Fig. 3A) and the absence of unidentified products in the HPLC chromatograms (Pao et al, 2000). Nalbuphine concentrations in blood increased proportionally with decreases in the levels of SDN and then reached a plateau within 1 h in all species, except in dogs (Fig.…”

Section: Hydrolysis Profiles Of Sdn In Bloodmentioning

confidence: 82%

“…The hydrolysis of the prodrug was stopped completely by the addition of the extraction solvent under 0°C as soon as samples were obtained. Both SDN and nalbuphine in plasma and blood were determined by the same HPLC method reported by Pao et al (2000). To evaluate the drug concentration in the red blood cells, the hematocrit of blood samples was measured immediately after the blood samples were collected.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma samples were immediately HPLC Assay. Both SDN and nalbuphine in plasma and whole blood were analyzed by high-performance liquid chromatography (Pao et al, 2000). Ultraviolet and fluorescence detectors were connected in series for determining SDN and nalbuphine, respectively.…”

Section: Methodsmentioning

confidence: 99%

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In Vitro and in Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine

Pao

Hsiong

et al. 2004

Drug Metab Dispos

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ABSTRACT:A diester prodrug of nalbuphine, sebacoyl dinalbuphine (SDN), and its long-acting formulation are currently being developed to prolong the duration of nalbuphine. A comparative in vitro hydrolysis study was conducted for SDN in rat, rabbit, dog, and human blood. Both SDN and nalbuphine in blood or plasma were measured by high-performance liquid chromatography. The hydrolysis rates of SDN in blood were ranked as follows: rat > rabbit > human > dog. The rapid formation of nalbuphine in the blood accounted for almost 100% of the prodrug, which supported the contention that nalbuphine is the major metabolite after SDN hydrolysis. The hydrolysis profiles of SDN were similar both in plasma and in red blood cells when compared in the blood. In vitro release results of SDN long-acting formulation showed that the rate-limited step of SDN hydrolysis to nalbuphine in blood is the penetration of SDN from oil into the blood. After intravenous administration of SDN in sesame oil into rats, nalbuphine quickly appeared in plasma and, thereafter, exhibited monoexponential decay. Pharmaceutical dosage forms affecting the drug disposition kinetics were demonstrated after intravenous administration. The AUC of nalbuphine was significantly higher and clearance was significantly lower, without changes in the t 1/2 of nalbuphine after intravenous dosing of SDN in sesame oil when compared with that of intravenous dosing with nalbuphine HCl in rats. Overall, these results suggest that SDN fulfilled the original pro-soft drug design in which the prodrug can rapidly metabolize to nalbuphine, and no other unexpected compounds were apparent in the blood.Esters have been the most common approach for prodrug development, because ester linkage of prodrugs tends to be converted efficiently to the active species through wide variability of esterase in the organs and tissues (Williams, 1985;Leinweber, 1987). The ester prodrugs apparently show that the safety and pharmacological actions of prodrugs seem to be the same as those for the parent compound (He et al., 1999;Ishikawa, 1999;Noble and Goa, 1999;Doucette and Aoki, 2001;Beaumont et al., 2003;Fischer et al., 2003). Nalbuphine is a potent -receptor agonist, -receptor antagonist analgesic with relatively low side effects (Jasinski and Mansky, 1972;Beaver and Feise, 1978). However, its short elimination half-life results in frequent injections for control of moderate to severe pain in clinical cases (Lo et al., 1987). SDN is a novel synthetic diester prodrug of nalbuphine designed to have high lipophilicity that consequently prolongs the duration of nalbuphine after intramuscular injection (Fig. 1).A successfully designed prodrug should not only be well absorbed, but should also metabolize primarily and readily to its active moiety. The prodrug should fulfill several criteria as proposed by Bodor (1984). Basically, no unexpected compound should be formed in vivo. Red blood cells and plasma are known to contain esterase (Leinweber, 1987;Cossum, 1988). In this study, SDN was examined for i...

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Section: Hydrolysis Profiles Of Sdn In Bloodmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

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In Vitro and in Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine

Pao

Hsiong

et al. 2004

Drug Metab Dispos

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“…As the available methods were found not be suitable for the simultaneous assay of nalbuphine and SDN, there was a need to develop an assay for the two analytes. Pao et al (2000) used a simple HPLC method with a one-step extaction scheme for the determination of the two agents in plasma. For the purpose of extraction, a mixture of N-hexane-isoamyl alcohol (9:1, v/v) was used and plasma was alkalinized with a mild buffer like sodium bicarbonate.…”

Section: Determination Of a Major Metabolite As A Surrogate For The Pmentioning

confidence: 99%

Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations

Srinivas

2006

Biomed. Chromatogr.

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The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select disease areas and/or in clinically important drug-drug interaction studies. A tabular representation of select examples of analysis is provided covering areas of separation conditions, validation aspects and applicable conclusion. A limited discussion is provided on relevant aspects of the need for developing bioanalytical procedures for speedy drug discovery and development. Additionally, some key elements such as internal standard selection, likely issues of mass detection, matrix effect, chiral aspects etc. are provided for consideration during method development.

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“…A few methods have been described to detect nalbuphine in pharmaceutical formulations; they include GC coupled to electron-capture detection, 26 or mass spectrometry, 27 HPLC with electrochemical detection, [28][29][30][31][32][33][34] and ion-selective electrode. 35 Although the GC methods, 26,27 are sensitive, they involved expensive equipments and time consuming samples preparation and are not easily available for regular drug monitoring.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Spectrophotometry Method for the Determination of Morphine, Nalbuphine and Naltrexone Drugs in Bulk and Pharmaceutical Formulations

El‐Didamony

Saad

Saleem

2013

J. Chil. Chem. Soc.

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A novel study describes the development and validation of a selective and simple kinetic spectrophotometric method for the determination of some analgesic drugs namely, morphine (MOF), nalbuphine (NAB) and naltrexone (NAT) in bulk and in pharmaceutical formulations. This method was based on the reaction of the drugs under studying with alkaline KMnO 4 to form a water-soluble bluish green colored product with a maximum absorbance at 605 nm. Although, the determination of MOF, NAB and NAT drugs by rate constant, fixed-concentration and fixed time methods were feasible with the calibration equations obtained, the fixed time method has been found to be more applicable. The fixed-time method is adopted for constructing the calibration curves, which were found to be linear over the concentration ranges of 4 -18 mg mL -1 MOF, 2 -20 mg mL -1 NAB and 2 -16 mg mL -1 NAT. Different experimental parameters which can affect the development and stability of the color were carefully studied and optimized. The fixed time method of 20 min was further applied to pharmaceutical formulations of each drug and the percentage recoveries were 99.85±0.049 to 102.27±0.024. Statistical comparisons of the results with the reference methods show the excellent agreement and indicate no significant difference in accuracy and precision.

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High-performance liquid chromatographic method for the simultaneous determination of nalbuphine and its prodrug, sebacoyl dinalbuphine ester, in dog plasma and application to pharmacokinetic studies in dogs

Cited by 23 publications

References 15 publications

In Vitro and in Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine

In Vitro and in Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine

Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations

Kinetic Spectrophotometry Method for the Determination of Morphine, Nalbuphine and Naltrexone Drugs in Bulk and Pharmaceutical Formulations

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