Evaluation of ketorolac concentrations in plasma and gingival crevicular fluid following topical treatment with oral rinses and dentifrices.
Two clinical studies were conducted to determine the relative amounts of ketorolac detectable locally in the gingival crevicular fluid (GCF) and systemically in plasma after oral, topical drug administration. The rinse study compared topical administration of three concentrations of ketorolac tromethamine (0.1%, 0.5%, and 0.01%) in oral rinse formulations administered topically and a perorally administered capsule (10 mg), and the dentifrice study compared two concentrations of ketorolac in dentifrice formulations (0.15% and 1.0%) with a 0.1% oral rinse, all treatments administered topically. The dose-corrected systemic availability of the three oral rinses evaluated in the rinse study relative to the peroral capsule was about 15%. However, the ratios of the observed maximum GCF ketorolac concentration to maximum plasma ketorolac concentration ranged from 22 to 49, compared to less than 1 for the peroral ketorolac capsule. Using this ratio as an estimate of the ability of a treatment to target the drug to the gingival tissue, these data indicate that the ketorolac oral rinses achieved greater delivery of drug to the gingival tissue (presumed site of action for periodontitis) with a lower systemic drug load than peroral administration of a ketorolac capsule. The dose-corrected relative systemic bioavailabilities for the dentifrice treatments with respect to the 0.1% rinse in the dentifrice study were 59.2% and 86.4% for the 1.0% and 0.15% dentifrices, respectively, indicating that significantly less ketorolac was systemically available from the two dentifrices relative to the oral rinse. The relative bioavailabilities of ketorolac in the GCF after dosing with the dentifrice formulations with respect to the rinse were 89.1% for the 1.0% dentifrice and 19.7% for the 0.15% dentifrice. Thus, the 1.0% dentifrice appears to provide statistically equivalent levels of ketorolac to the gingival tissue as the 0.1% oral rinse with significantly less systemic exposure. The T1/2 of ketorolac in the GCF was about 0.5 h for all three treatments, which is significantly less than the plasma half-life of about 5.3 h. These data suggest that GCF levels of ketorolac should remain above the IC50 for PGE2-stimulated IL-1 bone resorption for about 7 h following treatment, assuming continuation of the first-order elimination observed over the first two postdosing hours. We conclude that oral rinses and dentifrices are effective and preferred vehicles for administration of ketorolac for use in treatment of periodontitis.
Kelm
G R
GR
Miami Valley Laboratories, Procter & Gamble Co., Cincinnati, OH 45239-8707, USA.
Buchanan
W
W
Meredith
M P
MP
Offenbacher
S
S
Mankodi
S M
SM
Dobrozsi
D J
DJ
Bapat
N V
NV
Collins
J G
JG
Wehmeyer
K R
KR
Eichhold
T H
TH
Doyle
M J
MJ
D000287:Administration, Topical; D000328:Adult; D000368:Aged; D003802:Dentifrices; D004311:Double-Blind Method; D005883:Gingival Crevicular Fluid / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D020910:Ketorolac; D008875:Middle Aged; D009067:Mouthwashes; D010919:Placebos; D014046:Tolmetin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
D003802:Dentifrices; D009067:Mouthwashes; D010919:Placebos; D014046:Tolmetin; D020910:Ketorolac