In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man
Introduction
High blood pressure following cardiac surgery was first described by Estafanous et al. (1973). At that time, the authors recommended rapid and effective treatment of postoperative hypertensive episodes in an effort to reduce the risk of increased blood loss and haemorrhage from the vascular suture line. A more recently performed study (Vuylsteke et al., 1996a) showed that more than 80% of patients were treated at least once, during or immediately following the cardiac surgical procedure, to lower arterial blood pressure. The conclusion from that study was that routine cardio-thoracic anaesthesia practice is to reduce and maintain blood pressure at or below normal pre-operative levels rather than to treat hypertension (Vuylsteke et al., 1996b). The agents to be used for this indication need to have a rapid onset and recovery from effect to be able to control the blood pressure properly.
Clevidipine (Fig. 1) is a new ultrashort-acting calcium antagonist under clinical development, intended to be used intravenously for the reduction and control of blood pressure in connection with cardiac surgical procedures. Clevidipine is structurally related to another calcium antagonist of the dihydropyridine type, felodipine, but incorporation of an ester group in the drug molecule results in rapid hydrolysis of the compound by esterases in blood and extravascular tissues to the corresponding inactive metabolite (Nordlander, 1994) (Fig. 1). Clevidipine is a racemic mixture of two enantiomers, S- and R-clevidipine (Fig. 1).
During cardio-pulmonary bypass surgery, the patients are cooled to a lower body temperature and the blood is usually diluted (Nadjmabadi et al., 1978). Reports on other ester-containing compounds, i.e. esmolol and remifentanil, have shown lower hydrolysis rates during hypothermic cardio-pulmonary bypass surgery (Jacobs et al., 1993, Royston, 1995), and that plasma protein binding affects the hydrolysis rate of remifentanil in different biological matrices (Selinger et al., 1995). Due to the rapid hydrolysis of the ester linkage by esterases in the blood, questions regarding the potential involvement of pseudocholinesterase in the metabolism of clevidipine were raised.
The objective of this study was to determine the in vitro hydrolysis rate of clevidipine in blood from the rat, the dog and man, including volunteers with psueodocholinesterase deficiency, in different biological matrices. Furthermore, the hydrolysis rates of the enantiomers of clevidipine, the influence of temperature and dilution of the blood were evaluated and the protein binding of clevidipine determined.
Section snippets
Chemicals
Clevidipine and the reference compound and internal standard felodipine were manufactured at Astra Pharmaceutical Production AB (Södertälje, Sweden). The purity of clevidipine was 99.6% based on HPLC analysis. The purity of felodipine was 99.4%. Tritium-labelled felodipine, clevidipine, S-[3H]clevidipine, R-[3H]clevidipine, primary metabolite (H 152/81) and H 172/99 (internal standard for H 152/81) (Fig. 1) were synthesised at Astra Hässle AB (Sweden). The radiochemical purities of the
Results
Table 1 gives a summary of the in vitro half-lives obtained in the different experiments in this study.
Discussion
The in vitro pharmacokinetics of the ultrashort-acting calcium antagonist clevidipine were studied in different animal species and man.
Clevidipine hydrolysis resulted in the formation of an equivalent amount of a primary metabolite by cleavage of the ester group. The reaction was a first-order reaction.
The in vitro hydrolysis rate of clevidipine in blood was extremely rapid in all species studied, including volunteers with pseudocholinesterase deficiency, although the hydrolysis rates in the
Acknowledgements
The authors wish to thank Prof. Jörgen Viby-Mogensen and co-workers at the Danish Cholinesterase Research Unit for administration and supplying the blood samples from pseudocholinesterase deficient volunteers.
References (30)
- et al.
Thermal balance during cardiopulmonary bypass with moderate hypothermia in man
Br. J. Anaesth.
(1977) - et al.
Systemic hypertension following myocardial revascularization
Am. Heart J.
(1973) - et al.
Species differences in hydrolysis of isocarcacyclin methyl ester (TEI-9090) by blood esterases
Biochem. Pharmacol.
(1995) - et al.
Drug–protein binding studies. New trend in analytical and experimental methodology
J. Chromatogr. Biomed. Appl.
(1996) - et al.
The effect of long-chain alkyl betinates on the arylesterase-like activity of bovine serum albumin
Bioorg. Chem.
(1992) - et al.
The pharmacokinetics and extra-hepatic clearance of remifentanil, a short acting opioid agonist, in male beagle dogs during constant rate infusion
Drug Metab. Dispos.
(1996) - et al.
Pharmacokinetics of felodipine in patients with impaired renal function
Br. J. Clin. Pharmacol.
(1989) - Ericsson, H., Fakt, C., Höglund, L., Jolin-Mellgård, Å., Nordlander, M., Sunzel, M., Regårdh, C.G., 1998....
- Fakt, C., Stenhoff, H., 1998. Determination of an ultrashort-acting antihypertensive dihydropyridine in blood using...
- et al.
The pharmacokinetics of remifentanil alone and in combination with esmolol in the rat
Pharm. Res.
(1996)
Use of dodecyl sulfate as an esterase inhibitor before gas-chromatographic determination of labile β-adrenoceptor blocking drugs
Clin. Chem.
Effect of hypothermia and sampling site on blood esmolol concentrations
J. Clin. Pharmacol.
Identification of human plasma cholinesterase variants in 6.688 individuals using biochemical analysis
Acta Anesthesiol. Scand.
Possible physiological roles of carboxylic ester hydrolases
Drug Metab. Rev.
Cited by (61)
Drug and pro-drug substrates and pseudo-substrates of human butyrylcholinesterase
2023, Biochemical PharmacologyDevelopment and validation of samples stabilization strategy and LC-MS/MS method for simultaneous determination of clevidipine and its primary metabolite in human plasma: Application to clinical pharmacokinetic study in Chinese healthy volunteers
2020, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesCitation Excerpt :Firstly, we determined the drug concentration in plasma instead of in blood. The rate of hydrolysis of clevidipine is much higher in blood than in plasma, because the membrane or the cytosol of the red blood cells contains the most efficient esterase in hydrolyzing clevidipine to H152/81 [9,24]. Meanwhile, the concentration of a drug in plasma is more related to drug target action than in blood, that the drug existed in blood cells actually generates no effect on target.
Esterases
2018, Comprehensive Toxicology: Third EditionStudies on the competitive binding of cleviprex and flavonoids to plasma protein by multi-spectroscopic methods: A prediction of food-drug interaction
2017, Journal of Photochemistry and Photobiology B: BiologyCitation Excerpt :It has been reported that grapefruit juice can change the area under the curve ratio of cleviprex [22], which is indicative of further studies of food-cleviprex interactions are needed. The binding of cleviprex to plasma proteins is more than 99.5% [23], which indicates that the factors can alter the affinity of cleviprex binding to plasma proteins should be considered in clinic. In addition, it has been reported that the flavonoids intake from the foods and beverages of people is concerning 0.67 g/day [10].
Simultaneous determination of clevidipine and its primary metabolite in dog plasma by liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic study
2014, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :Recent studies have found that both clevidipine and H152/81 can induce or inhibit CYP3A4 [10], hence there is a need to determine both the parent drug clevidipine and its primary metabolite H152/81, especially in combination therapy, which is very common in subjects with cardiovascular disease or in the case of cardiac surgery. The determination of clevidipine or H152/81 levels individually has been previously performed through HPLC methods with UV [11,12] or fluorescence detection [13,14]. Gas chromatography (GC) with electron-capture detection (ECD) [15] or mass spectrometry (MS) [13] is also an alternative for the determination of clevidipine.
Quantitation of clevidipine in dog blood by liquid chromatography tandem mass spectrometry: Application to a pharmacokinetic study
2014, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences