In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man

Ericsson, Henrik; Tholander, Bengt; Regårdh, C G

doi:10.1016/s0928-0987(98)00058-x

Cited by 62 publications

(49 citation statements)

References 17 publications

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“…Although stable in human plasma, PGE 2 -G was catabolized in human whole blood with a half-life of ϳ7 min. Enhanced ester lability in human whole blood when compared with plasma has been reported for both prostanoid and non-prostanoid esters and suggests a role for blood cells in glyceryl PG metabolism in humans (25)(26)(27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 98%

Metabolism of Prostaglandin Glycerol Esters and Prostaglandin Ethanolamides in Vitro and in Vivo

Kozak¹,

Crews²,

Ray³

et al. 2001

Journal of Biological Chemistry

125

111

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Prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs) are generated by the action of cyclooxygenase-2 on the endocannabinoids 2-arachidonylglycerol (2-AG) and arachidonylethanolamide, respectively. These novel eicosanoids may have unique pharmacological properties and/or serve as latent sources of prostaglandins at sites remote from their tissue of origin. Therefore, we investigated the metabolism of PG-Gs and PG-EAs in vitro and in vivo. PGE 2 -G was rapidly hydrolyzed in rat plasma to generate PGE 2 (t1 ⁄2 ‫؍‬ 14 s) but was only slowly metabolized in human plasma (t1 ⁄2 Ͼ 10 min). An intermediate extent of metabolism of PGE 2 -G was observed in human whole blood (t1 ⁄2 Ϸ 7 min). The parent arachidonylglycerol, 2-AG, and the more stable regioisomer, 1-AG, also were much more rapidly metabolized in rat plasma compared with human plasma. PGE 2 -EA was not significantly hydrolyzed in plasma, undergoing slow dehydration/isomerization to PGB 2 -EA. Both PGE 2 -G and PGE 2 -EA were stable in canine, bovine, and human cerebrospinal fluid. Human 15-hydroxyprostaglandin dehydrogenase, the enzyme responsible for the initial step in PG inactivation in vivo, oxidized both PGE 2 -G and PGE 2 -EA less efficiently than the free acid. The sterically hindered glyceryl prostaglandin was the poorest substrate examined in the E series. Minimal 15-hydroxyprostaglandin dehydrogenase oxidation of PGF 2␣ -G was observed. PGE 2 -G and PGE 2 -EA pharmacokinetics were assessed in rats. PGE 2 -G was not detected in plasma 5 min following an intravenous dose of 2 mg/kg. However, PGE 2 -EA was detectable up to 2 h following an identical dose, displaying a large apparent volume of distribution and a halflife of over 6 min. The results suggest that endocannabinoid-derived PG-like compounds may be sufficiently stable in humans to exert actions systemically. Furthermore, these results suggest that the rat is not an adequate model for investigating the biological activities of 2-arachidonylglycerol or glyceryl prostaglandins in humans.

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Section: Discussionmentioning

confidence: 98%

Metabolism of Prostaglandin Glycerol Esters and Prostaglandin Ethanolamides in Vitro and in Vivo

Kozak¹,

Crews²,

Ray³

et al. 2001

Journal of Biological Chemistry

125

111

View full text Add to dashboard Cite

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“…The half-life of clevidipine increases with lower blood temperatures. Clevidipine is highly protein-bound in human plasma (~99.7%) (18). No concentration-dependent protein binding of clevidipine has been observed in the dose range studied (18).…”

Section: Metabolismmentioning

confidence: 90%

Pharmacodynamic, Pharmacokinetic and Clinical Effects of Clevidipine, an Ultrashort‐Acting Calcium Antagonist for Rapid Blood Pressure Control

Nordlander

Sjöquist

Ericsson

et al. 2004

Cardiovascular Drug Reviews

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Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg). and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min.Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not increase heart rate.In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with clevidipine than with sodium nitroprusside.

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“…(Owen and Natatsu, 1983;Awasthi and Singh, 1984;Mieyal, 1985;Helander and Tottmar, 1987;Ericsson et al, 1999). Atul et al (2002) reported that the same metabolite of centpropazine was formed in rat liver S9, intestine, and RBCs.…”

Section: Miao Et Almentioning

confidence: 99%

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Miao¹,

Song²,

Savage³

et al. 2008

Drug Metab Dispos

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ABSTRACT:3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; ␤-lapachone) showed promising anticancer activity in phase I clinical trials as monotherapy and in combination with cytotoxic drugs. ARQ 501 is currently in multiple phase II clinical trials. In vitro incubation in fresh whole blood at 37°C revealed that ARQ 501 is stable in plasma but disappears rapidly in whole blood. Our data showed that extensive metabolism in red blood cells (RBCs) was mainly responsible for the rapid disappearance of ARQ 501 in whole blood. By comparison, covalent binding of ARQ 501 and/or its metabolites to whole blood components was a minor contributor to the disappearance of this compound. Sequestration of intact ARQ 501 in RBCs was not observed. Cross-species metabolite profiles from incubating [ 14 C]ARQ 501 in freshly drawn blood were characterized using a liquid chromatography-mass spectrometry-accurate radioactivity counter. The results show that ARQ 501 was metabolized more rapidly in mouse and rat blood than in dog, monkey, and human blood, with qualitatively similar metabolite profiles. Six metabolites were identified in human blood using ultra-high performance liquid chromatography/time-of-flight mass spectrometry, and the postulated structure of five metabolites was confirmed using synthetic standards. We conclude that the primary metabolic pathway of ARQ 501 in human blood involved oxidation of the two adjacent carbonyl groups to produce dicarboxylic and monocarboxylic metabolites, elimination of a carbonyl group to form a ring-contracted metabolite, and lactonization to produce two metabolites with a pyrone ring to form a ring-contracted metabolite. Metabolism by RBCs may play a role in clearance of ARQ 501 from the blood compartment in cancer patients.

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In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man

Cited by 62 publications

References 17 publications

Metabolism of Prostaglandin Glycerol Esters and Prostaglandin Ethanolamides in Vitro and in Vivo

Metabolism of Prostaglandin Glycerol Esters and Prostaglandin Ethanolamides in Vitro and in Vivo

Pharmacodynamic, Pharmacokinetic and Clinical Effects of Clevidipine, an Ultrashort‐Acting Calcium Antagonist for Rapid Blood Pressure Control

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

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