Determination of local tissue concentrations of bupivacaine released from biodegradable microspheres and the effect of vasoactive compounds on bupivacaine tissue clearance studied by microdialysis sampling

• Published in: Pharmaceutical research 2002-11, Vol.19 (11), p.1745-1752
• Main Authors: MCDONALD, Sarah, FAIBUSHEVICH, Alexander A, GARNICK, Susan, MCLAUGHLIN, Kieran, LUNTE, Craig
• Format: Article
• Language: English
• Subjects: Analgesics; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Bupivacaine - administration & dosage; Bupivacaine - pharmacokinetics; Dialysate; Drug Delivery Systems - methods; Efficiency; Female; General pharmacology; Ketamine; Laboratory animals; Medical sciences; Metabolic Clearance Rate - drug effects; Metabolic Clearance Rate - physiology; Microdialysis - methods; Microspheres; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Neuropharmacology; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Skin; Surgical apparatus & instruments; Tissue Distribution - drug effects; Tissue Distribution - physiology; Vasoconstrictor Agents - administration & dosage; Vasoconstrictor Agents - pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1020725917197

Incorporation of bupivacaine, a short acting local analgesic, into injectable microspheres provides a long acting formulation. Co-incorporation of dexamethasone into the microspheres results in extended activity. The purpose of this study is to compare tissue concentrations of bupivacaine resulting from the two types of microspheres and to determine if the observed sustained tissue concentration of bupivacaine is due to changes in its tissue clearance. Microdialysis probes were implanted into rat muscle. Following microsphere injection, bupivacaine tissue concentration was monitored (HPLC-UV), and the tissues histologically examined. The effect of vasoactive compounds on the tissue concentration of bupivacaine, not formulated in microspheres, was monitored. Hind muscle histology showed significant granulomatous reactions around the probe and both types of microspheres. A higher, prolonged bupivacaine concentration was observed from microspheres. A higher, prolonged bupivacaine concentration was observed from microspheres with co-incorporated dexamethasone relative to those without dexamethasone. Addition of vasoconstrictors to the perfusate containing bupivacaine resulted in decreased bupivacaine delivery compared to bupivacaine alone, whereas the addition of a vasodilator increased bupivacaine delivery. The longer lasting effect of microspheres with co-incorporated dexamethasone results from higher, prolonged tissue concentrations of bupivacaine. Dexamethasone, a vasoconstrictor, decreases the clearance rate of bupivacaine from the tissue resulting in a higher, prolonged tissue concentration of bupivacaine.