Electroencephalographic Recovery, Hypnotic Emergence, and the Effects of Metabolite after Continuous Infusions of a Rapidly Metabolized Etomidate Analog in Rats

被引：33

作者：

Pejo, Ervin ^{[1
]}

Ge, Rile ^{[1
]}

Banacos, Natalie ^{[1
]}

Cotten, Joseph F. ^{[1
,2
]}

Husain, S. Shaukat ^{[1
,2
]}

Raines, Douglas E. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Boston, MA USA

来源：

ANESTHESIOLOGY | 2012年 / 116卷 / 05期

基金：

美国国家卫生研究院;

关键词：

INTRAVENOUS ANESTHESIA; RENAL-FAILURE; PHARMACOKINETICS; REMIFENTANIL; PHARMACODYNAMICS; SUPPRESSION; VOLUNTEERS; ALFENTANIL; ESMOLOL; DESIGN;

D O I：

10.1097/ALN.0b013e3182515403

中图分类号：

R614 [麻醉学];

学科分类号：

100217 [麻醉学];

摘要：

Background: Methoxycarbonyl etomidate is an ultrarapidly metabolized etomidate analog. It is metabolized to methoxycarbonyl etomidate carboxylic acid (MOC-ECA), which has a hypnotic potency that is 350-fold less than that of methoxycarbonyl etomidate. The authors explored the relationships between methoxycarbonyl etomidate infusion duration, recovery time, metabolite concentrations in blood and cerebrospinal fluid (CSF), and methoxycarbonyl etomidate metabolism in brain tissue and CSF to test the hypothesis that rapid metabolism of methoxycarbonyl etomidate may lead to sufficient accumulation of MOC-ECA in the brain to produce a pharmacologic effect. Methods: A closed-loop system with burst suppression ratio feedback was used to administer methoxycarbonyl etomidate infusions of varying durations to rats. After infusion, recovery of the electroencephalogram and righting reflexes were assessed. MOC-ECA concentrations were measured in blood and CSF during and after methoxycarbonyl etomidate infusion, and the in vitro half-life of methoxycarbonyl etomidate was determined in rat brain tissue and CSF. Results: Upon termination of continuous methoxycarbonyl etomidate infusions, the burst suppression ratio recovered in a biexponential manner with fast and slow components having time constants that differed by more than 100-fold and amplitudes that varied inversely with infusion duration. MOC-ECA concentrations reached hypnotic concentrations in the CSF with prolonged methoxycarbonyl etomidate infusion and then decreased during a period of several hours after infusion termination. The metabolic half-life of methoxycarbonyl etomidate in brain tissue and CSF was 11 and 20 min, respectively. Conclusion: In rats, methoxycarbonyl etomidate metabolism is sufficiently fast to produce pharmacologically active MOC-ECA concentrations in the brain with prolonged methoxycarbonyl etomidate infusion.

引用

页码：1057 / 1065

页数：9

共 22 条

[1]

[Anonymous], 1994, INT C HARM TECHN REQ

[2]

Bodor N, 2000, MED RES REV, V20, P58, DOI 10.1002/(SICI)1098-1128(200001)20:1<58::AID-MED3>3.0.CO

[3]

2-X

[4]

ETOMIDATE AND PLASMA ESTERASE-ACTIVITY IN MAN AND EXPERIMENTAL-ANIMALS [J].

CALVO, R ;

CARLOS, R ;

ERILL, S .

PHARMACOLOGY, 1979, 18 (06) :294-298

[5]

Closed-loop Continuous Infusions of Etomidate and Etomidate Analogs in Rats A Comparative Study of Dosing and the Impact on Adrenocortical Function [J].

Cotten, Joseph F. ;

Le Ge, Ri ;

Banacos, Natalie ;

Pejo, Ervin ;

Husain, S. Shaukat ;

Williams, James H. ;

Raines, Douglas E. .

ANESTHESIOLOGY, 2011, 115 (04) :764-773

[6]

Methoxycarbonyl-etomidate A Novel Rapidly Metabolized and Ultra-short-acting Etomidate Analogue that Does Not Produce Prolonged Adrenocortical Suppression [J].

Cotten, Joseph F. ;

Husain, S. Shaukat ;

Forman, Stuart A. ;

Miller, Keith W. ;

Kelly, Elizabeth W. ;

Nguyen, Hieu H. ;

Raines, Douglas E. .

ANESTHESIOLOGY, 2009, 111 (02) :240-249

[7]

Remifentanil versus alfentanil - Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers [J].

Egan, TD ;

Minto, CF ;

Hermann, DJ ;

Barr, J ;

Muir, KT ;

Shafer, SL .

ANESTHESIOLOGY, 1996, 84 (04) :821-833

[8]

Tutorial: Context-sensitive decrement times for inhaled anesthetics [J].

Eger, EI ;

Shafer, SL .

ANESTHESIA AND ANALGESIA, 2005, 101 (03) :688-696

[9]

DESIGN, SYNTHESIS, AND PHARMACOLOGICAL EVALUATION OF ULTRASHORT-ACTING TO LONG-ACTING OPIOID ANALGESICS [J].

FELDMAN, PL ;

JAMES, MK ;

BRACKEEN, MF ;

BILOTTA, JM ;

SCHUSTER, SV ;

LAHEY, AP ;

LUTZ, MW ;

JOHNSON, MR ;

LEIGHTON, HJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (07) :2202-2208

[10]

PHARMACOKINETICS OF ESMOLOL AND ASL-8123 IN RENAL-FAILURE [J].

FLAHERTY, JF ;

WONG, B ;

LAFOLLETTE, G ;

WARNOCK, DG ;

HULSE, JD ;

GAMBERTOGLIO, JG .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 1989, 45 (03) :321-327

← 1 2 3 →