Pharmacokinetics and Arteriovenous Differences in Clevidipine Concentration following a Short- and a Long-term Intravenous Infusion in Healthy Volunteers

Ericsson, Henrik; Bredberg, Ulf; Eriksson, Ulf G.; Jolin‐Mellgård, Å.; Nordlander, Margareta; Regårdh, C G

doi:10.1097/00000542-200004000-00016

Cited by 49 publications

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“…These results suggest that clevidipine has suitable attributes to become a useful novel therapeutic agent for use in acute care situations requiring rapid blood pressure control. (14).…”

Section: Discussionmentioning

confidence: 99%

“…The steady state volume of distribution (V ss ) for clevidipine derived from arterial and venous blood concentrations is listed in Table 3 (14). The mean V ss of clevidipine derived from venous blood is larger than that derived from arterial blood.…”

Section: Volume Of Distribution and Clearancementioning

confidence: 99%

“…As shown in Table 3, the half-lives associated with the exponential phases of the blood concentration vs. time curve vary slightly in different studies (12,14). However, characterizing pharmacokinetics of a drug with disposition models containing two or three exponential phases with different half-lives is sometimes done by arbitrary judgments.…”

Section: Half-life and Decrement Timesmentioning

confidence: 99%

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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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“…These results suggest that clevidipine has suitable attributes to become a useful novel therapeutic agent for use in acute care situations requiring rapid blood pressure control. (14).…”

Section: Discussionmentioning

confidence: 99%

Section: Volume Of Distribution and Clearancementioning

confidence: 99%

Section: Half-life and Decrement Timesmentioning

confidence: 99%

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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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“…It has been suggested that an inhibition interaction in vivo would "likely" occur if the ratio of inhibitor C max /K i was greater than 1 (Bjornsson et al, 2003), "possible" if the ratio is between 1 and 0.1, and "remote" if below 0.1. A long-term (24-h) intravenous infusion with CLE at 7 nmol/min/kg in healthy volunteers showed that the steady-state blood concentrations were approximately 0.1 M with a rapid clearance after the infusion was stopped (Ericsson et al, 2000). The [I]/K i ratios of CLE CYP2C19 and CYP3A4/testosterone were found to be less than 0.1, whereas for CYP2C9 and CYP3A4/midazolam, the corresponding values were 0.18 and 0.1, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…1), is in phase III clinical trials as a rapid acting calcium channel antagonist for intravenous control of blood pressure (Nordlander et al, 2004). Clevidipine is rapidly hydrolyzed and inactivated by esterases in blood and extravascular tissues to its primary metabolite H152/81 (Ericsson et al, 1999(Ericsson et al, , 2000. CLE may have advantages over other antihypertensives.…”

Section: Introductionmentioning

confidence: 99%

Human Cytochrome P450 Induction and Inhibition Potential of Clevidipine and Its Primary Metabolite H152/81

Zhang

Dehal²,

Ho³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Clevidipine is a short-acting dihydropyridine calcium channel antagonist under development for treatment of perioperative hypertension. Patients treated with clevidipine are likely to be comedicated. Therefore, the potential for clevidipine and its major metabolite H152/81 to elicit drug interactions by induction or inhibition of cytochrome P450 was investigated. Induction of CYP1A2, CYP2C9, and CYP3A4 was examined in primary human hepatocytes treated with clevidipine at 1, 10, and 100 M. Clevidipine was found to be an inducer of CYP3A4, but not of CYP1A2 or CYP2C9, at the 10 M and 100 M concentrations of clevidipine tested. Induction response for CYP3A4 to 100 M clevidipine was approximately 20% of that of the positive control inducer rifampicin. The response of H152/81 was similar. Using cDNA-expressed enzymes, clevidipine inhibited CYP2C9, CYP2C19, and CYP3A4 activities with IC 50 values below 10 M, whereas CYP1A2, CYP2D6, and CYP2E1 activities were not substantially inhibited (IC 50 values >70 M). The K i values for CYP2C9 and CYP2C19 were 1.7 and 3.3 M, respectively, and those for CYP3A4 were 8.3 and 2.9 M, using two substrates, testosterone and midazolam, respectively. These values are at least 10 times higher than the highest clevidipine concentration typically seen in the clinic. Little or no inhibition by H152/81 was found for the enzyme activities mentioned above (IC 50 values > 69 M). The present study demonstrates that it is highly unlikely for clevidipine or its major metabolite to cause cytochrome P450-related drug interactions when used in the dose range required to manage hypertension in humans.Clevidipine (CLE), butyroxymethyl methyl 4-(2Ј, 3Ј-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ( Fig. 1), is in phase III clinical trials as a rapid acting calcium channel antagonist for intravenous control of blood pressure (Nordlander et al., 2004). Clevidipine is rapidly hydrolyzed and inactivated by esterases in blood and extravascular tissues to its primary metabolite H152/81 (Ericsson et al., 1999(Ericsson et al., , 2000. CLE may have advantages over other antihypertensives. For example, CLE effectively controlled blood pressure in hypertensive patients after undergoing elective coronary bypass grafting, and hemodynamic changes were less pronounced with CLE, compared with sodium nitroprusside (Powroznyk et al., 2003). CLE successfully decreased systemic vascular resistance and mean arterial pressure without changing heart rate, cardiac index, or cardiac filling pressures (Bailey et al., 2002).Clevidipine is a member of the dihydropyridine class of compounds, which have been shown to be inducers and/or inhibitors of cytochromes P450. For example, nifedipine, nicardipine, and isradipine are potent inducers for CYP3A4, CYP2B, and CYP2C in human hepatocyte cultures (Drocourt et al., 2001), and nifedipine induces CYP2C in coronary artery segment endothelial cells (Fisslthaler et al., 2000). In addition, nicardipine, benidipine, manifipine, and barnidipine are potent inhibit...

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Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients

et al. 2001

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The aim of the study was to characterize the individual pharmacokinetics of (-)-R- and (+)-S-clevidipine following intravenous constant rate infusion of rac-clevidipine to essential hypertensive patients. Twenty patients received three out of five randomized treatments with clevidipine. The pharmacokinetics of the separate enantiomers were evaluated by compartmental analysis of blood concentrations vs. time curves using the population approach. The derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-clevidipine. A two-compartment model was used to describe the dispositions of the enantiomers; there were only minor differences between the estimated pharmacokinetic parameters of the separate enantiomers. The mean blood clearance values of (-)-R- and (+)-S-clevidipine were 0.103 and 0.096 l/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0.54 l/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concentration was achieved approximately 8 min postinfusion for (-)-R-clevidipine and 11 min for (+)-S-clevidipine, following clinically relevant infusion times with clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution for the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a single enantiomer as an alternative to the racemic clevidipine will not offer any clinical advantages.

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Pharmacokinetics and Arteriovenous Differences in Clevidipine Concentration following a Short- and a Long-term Intravenous Infusion in Healthy Volunteers

Cited by 49 publications

References 0 publications

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

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

Human Cytochrome P450 Induction and Inhibition Potential of Clevidipine and Its Primary Metabolite H152/81

Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients

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