Simultaneous determination of bosentan and its three major metabolites in various biological matrices and species using narrow bore liquid chromatography with ion spray tandem mass spectrometric detection.

Lausecker, Berthold; Hess, B.; Fischer, G.; Mueller, Markus; Hopfgartner, Gérard

doi:10.1016/s0378-4347(00)00386-8

Cited by 36 publications

(21 citation statements)

References 10 publications

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“…The analysis of rat plasma samples and samples from in vitro experiments was done with LC-MS/MS using a modified method published previously (Lausecker et al, 2000). Plasma and microsomal proteins were precipitated with ice-cold acetonitrile containing known quantities of the tetra-deuterated analogs of bosentan and its metabolites Ro 48-5033 and Ro 47-8634 as internal standards, vortexing for 20 min, and centrifugation at 4000 rpm for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat

Treiber

Schneiter²,

Delahaye³

et al. 2003

J Pharmacol Exp Ther

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In clinical trials, a significant interaction between the endothelin receptor antagonist bosentan and the immunosuppressant cyclosporin A was observed, which could not be rationalized in terms of inhibition of drug-metabolizing enzymes. We present here a study performed in rats investigating the mechanisms underlying this interaction, including the inhibition of active drug transport processes as part of the gastrointestinal absorption and disposition into the liver. In vitro, the majority of bosentan uptake into liver cells was shown to depend on active transport and to be efficiently inhibited by cyclosporin A. All known members of the organic anion transporting polypeptide (oatp) transport protein family expressed in rat liver, i.e., oatp1, oatp2, and oatp4, were shown to be involved in the uptake of bosentan. Results from both series of experiments point to inhibition of active bosentan uptake into the liver by cyclosporin A as the major underlying mechanism for this pharmacokinetic interaction that is in line with reports on other oatp-transported drugs. Significant contributions of other mechanisms such as inhibition of mdr1-mediated drug efflux during gastrointestinal absorption, inhibition of bosentan metabolism, or inhibition of hepatobiliary excretion seemed to be unlikely. The interaction between bosentan and cyclosporin A is a rare example of a pharmacokinetic interaction, which can mostly be attributed to the inhibition of transport processes in the liver. It also demonstrates that inhibition of uptake into the liver might become rate-limiting in the overall elimination process even for compounds whose clearance is dependent on metabolism. The relevance of these findings in the rat for clinical use remains to be explored. It is, however, clear that inhibition of CYP3A4-mediated metabolism by cyclosporin A alone is insufficient to explain the increased bosentan concentrations and that inhibition of hepatocellular uptake offers an attractive mechanistic alternative also in human.Bosentan (Tracleer) is a dual endothelin receptor antagonist (Clozel et al., 1994;Neidhart et al., 1996) approved as the first oral treatment for pulmonary arterial hypertension (Rubin et al., 2002). During the clinical development of bosentan, the potential interaction between bosentan (500 mg b.i.d.) with the immunosuppressant cyclosporin A (300 mg b.i.d.) has been investigated in healthy male volunteers. After the 1st day of concomitant dosing, a 30-fold increase of bosentan trough plasma concentrations was observed compared with volunteers receiving bosentan alone. In humans, bosentan is extensively metabolized by the cytochrome P450 isoforms 2C9 and 3A4 before excretion into bile, the latter process accounting for more than 90% of total drug elimination. Cyclosporin A is a known inhibitor of CYP3A4 (Wacher et al., 1998) and the observed pharmacokinetic interaction was initially assigned to the inhibition of CYP3A4-mediated clearance in the liver. However, in another interaction study with the potent CYP3A4 inhibit...

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Section: Methodsmentioning

confidence: 99%

Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat

Treiber

Schneiter²,

Delahaye³

et al. 2003

J Pharmacol Exp Ther

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“…As seen in Table 8, the previously proposed method 30 is not able to cover the therapeutic range and this complementary work is conducted to decrease the LOQs and provides a practical analytical method to determine bosentan without interference from other compounds present in the samples. In the literature, 6,7,9 two kinds of sample preparation methods such as liquid-liquid extraction and solid phase extraction have been developed. Nevertheless, these conventional extraction methods are time-consuming and require large volumes of samples and toxic organic solvents.…”

Section: Comparison With Other Workmentioning

confidence: 99%

“…DLLME and USAEME are easy, solvent and cost saving procedures. In spite of developments in modern analytical instruments [6][7][8][9] with better LLOQs and linearity ranges, high cost of analysis make them not applicable for routine clinical applications. These microextraction methods also provided reasonable results for extraction of aluminum from urine samples after complexation with 8-hydroxy quinoline.…”

Section: Comparison With Other Workmentioning

confidence: 99%

“…Liquid chromatography-mass spectrometry, 6,7 ultra performance liquid chromatography, 8 narrow bore high performance liquid chromatography, 9 ultrafast liquid chromatography 10 methods are available for determination of bosentan in plasma samples. Although reported methods are sensitive, they employ more expensive setups and are not available to be used in biomedical laboratories.…”

Section: Introductionmentioning

confidence: 99%

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Development and Validation of Ultrasound Assisted and Dispersive Liquid-Liquid Microextractions Combined with HPLC-UV Method for Determination of Bosentan in Human Plasma and Urine

Sajedi-Amin

Asadpour‐Zeynali

Khoubnasabjafari

et al. 2016

J. Braz. Chem. Soc.

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A feasible, rapid, sensitive and reliable dispersive liquid-liquid microextraction (DLLME) and ultrasonic assisted liquid-liquid microextraction (USAEME) combined with high-performance liquid chromatography (HPLC) method with UV detection was developed and validated for analysis of bosentan in human plasma and urine samples. All validation tests were reported according to FDA guidelines. Since chromatographic methods are precise, accurate and provide excellent separation are increasingly being used in determination of trace amount of drugs in biological goals. So the optimized experimental extraction factors from our previous work were used to evaluate HPLC-UV method for decreasing the limit of quantifications (LOQs) to cover the therapeutic range. Simple centrifugation of urine samples was sufficient prior to microextraction procedure, while acetonitrile protein precipitation provides sample clean up for plasma samples. The suggested method was linear (correlation coefficient R 2 > 0.998) over a range of 0.1-10 μg mL -1 which covers the therapeutic range. Proposed methods are practical for quantitative analysis of bosentan in real samples, and could be used in routine clinical analyses.

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“…The reported methods are sensitive but are having disadvantages like a narrow range of linear response, more retention time and lesser precision. Two narrow-bore LC-MS methods were reported (Lausecker et al, 1995, Lausecker et al, 2000. The reported LC-MS methods involve costly detector and tiresome sample preparation steps.…”

Section: Introductionmentioning

confidence: 99%

Estimation of Bosentan Monohydrate in Male Rabbit Plasma by using RP-HPLC Method

2017

J App Pharm Sci

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A new method for the quantitative determination of bosentan monohydrate in male rabbit plasma was developed by Reverse Phase HPLC as per standard regulatory guidelines. Precipitation method was used for extracting the drug from the drug spiked plasma using mobile phase. The analyte extracted was injected in to ODS column C18 (250 x 4.6 mm, 5µm), temperature was maintained at 25 0 C and monitoring of effluent was performed at 273 nm. The mobile phase consist acetonitrile and phosphate buffer (pH 4.6) in 80:20 ratio. The method developed shown high specificity for bosentan monohydrate. The calibration curve for bosentan monohydrate was linear from 0.1-5 µg/0.5mL in plasma (R 2 =0.9999). The lower limit of detection is 0.1µg/0.5mL. Developed method was verified for precision in intra-day and inter-day and was found within the limits. The accuracy of the developed Reverse Phase HPLC method was found to be 99.8±1.25-98.7±1.29% and is found to be reproducible. The method developed was proved to be adequate, sensitive and reproducible for the determination of bosentan monohydrate in rabbit plasma.

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Simultaneous determination of bosentan and its three major metabolites in various biological matrices and species using narrow bore liquid chromatography with ion spray tandem mass spectrometric detection.

Cited by 36 publications

References 10 publications

Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat

Inhibition of Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake Is the Major Determinant in the Pharmacokinetic Interaction between Bosentan and Cyclosporin A in the Rat

Development and Validation of Ultrasound Assisted and Dispersive Liquid-Liquid Microextractions Combined with HPLC-UV Method for Determination of Bosentan in Human Plasma and Urine

Estimation of Bosentan Monohydrate in Male Rabbit Plasma by using RP-HPLC Method

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