Use of 2-hydroxypropyl-beta-cyclodextrin as an intrathecal drug vehicle with opioids.
2-Hydroxypropyl-beta-cyclodextrin (CDEX), a seven-membered glucose pyranose structure, forms reversible inclusion complexes with the lipophilic portion of a drug molecule by noncovalent bonding. This can increase the water solubility of lipid-soluble drugs and reduce the rate of clearance of such agents from the spinal cord into the vasculature after i.t. administration. In this study, opioids (morphine, lofentanil, alfentanil and sufentanil) with and without CDEX (20, 2, 0.2 and 0.02% w/v in sterile water) were administered spinally in rats prepared with chronic i.t. catheters. CDEX prolonged the duration of analgesia (52.5 degrees C hot plate) and reduced the incidence of catalepsy otherwise produced by a supermaximal i.t. dose of each of the opioids. The magnitude of the potentiating effect of CDEX on opioids was dependent upon concentration of the CDEX and varied with drug lipid partition coefficients. The highest concentration of CDEX alone (20%) had no effect upon the volume-evoked micturition reflex, blood pressure, heart rate, or spinal reflexes. Our data indicate that CDEX may be a useful i.t. vehicle for modifying the redistribution characteristics of highly diffusible molecules after their i.t. administration, and that for each drug there is an optimal CDEX concentration. In the present case, CDEX prolongs the spinal analgesic action and reduces the supraspinal actions of i.t. drugs.
Department of Anesthesiology, University of California, San Diego, La Jolla.
J
J
Jang
T L
TL
Yaksh
H F
HF
Hill
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D015360:Analgesia, Epidural; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced; D003505:Cyclodextrins / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D006439:Hemodynamics / Q000187:drug effects; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D047392:beta-Cyclodextrins
D000701:Analgesics, Opioid; D003505:Cyclodextrins; D004337:Drug Carriers; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D009020:Morphine