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7/21/2019 Epilepsia Volume 36 Issue 3 1995 [Doi 10.1111%2Fj.1528-1157.1995.Tb00993.x] Wolfgang Lscher; Dagmar Hn
1/7
Epilepsia,
36(3):255-261, 1995
Raven P ress,
Ltd.,
N e w
Yofk
International League Ag am t
Epilepsy
New Injectable Aq ueous C arbam azepine Solution Through
Com plexing with
2-Hydroxypropyl-~-Cyclodextrin:
Tolerabili ty and Pharm acokinetics After Intra ve no us
Injection in C om parison
to a
Glycofurol-Based Formulation
Wolfgang Loscher, Dagmar Honack, Angelika Richter, *Hans-Ulrich Schulz,
Michael Schurer, fRaija Dusing, and $Marcus
E.
Brewster
Department of Pharma cology, Toxicology and Pharma cy, School of Veterinary Medicine , Hannover;
LAFAA
Laboratory fo r Contract Research in Clinical Pharmacology and Biopharmaceutical Analytics G m bH , Bad
Schwartau; fDesit in Arzneimittel Gm bH Hambu rg, German y; and SPharmos, Alachu a, Florida, U .S .A .
Summary: The poor water solubility of the antiepileptic
drug (AED) carbama zepine (CBZ) is generally considered
an absolu te contraindication to pa renteral administration
in epileptic patients. However, the water solubility of
CBZ can be largely enhanced through formation of an
inclusion complex with an a morp hous cyclodextrin deriv-
ative,
2-hydroxypropyl-~-cyclodextrin
HPPCD) . W e
studied tolerability and pharmacokinetics of an aqueous
CBZ:HPPCD solution afte r intravenous (i.v.) administra-
tion in dogs. For comparison,
a
conve ntiona l glycofurol-
based solution of CBZ wa s used. We also administered a
commercial liquid formulation of CB Z orally p.0.).nfu-
sion of CBZ:HPPC D solutions or HPP CD placebo for-
mulations i.v. was well tolerated by t he animals. In con-
trast, infusion of CB Z:glycofurol solutions and glycofurol
placebo solutions induced ma rked behavioral and cardio-
vascular adverse effects. Pharmacokinetic studies indi-
cated that glycofurol inhibited CBZ metabolism by de-
creasing formation of the major CBZ metabolite CBZ-
10,ll- epo xide (CBZ-E). With infusion of CBZ:HPPCD 10
ml/min for 12-15 min , resulting in
a
CBZ dose of CBZ 5
mg/kg body weight, peak CBZ plasma levels of -3.6 pgl
ml were obtained. This relatively low peak concentration
is primarily due to the rapid elimination of CBZ in dogs
[half-life (t )