Uptake of metronidazole by human gingival fibroblasts.
BACKGROUND
Metronidazole is an important antimicrobial agent for the therapeutic management of periodontal diseases and dentoalveolar infections. As in other tissues, the metronidazole concentration in gingival crevicular fluid is about equal to the plasma level. Thus, we hypothesized that metronidazole is not actively transported into human gingival fibroblasts.


METHODS
Using high performance liquid chromatography, the influences of extracellular metronidazole concentrations, temperature, pH, and inhibitors of transporters on the uptake of metronidazole by cultured human gingival fibroblasts were tested.


RESULTS
Metronidazole was taken up rapidly by fibroblasts; the intracellular metronidazole concentration reached the extracellular level in 3 minutes at 37 degrees C and in 2 minutes at 4 degrees C. The uptake of metronidazole by human gingival fibroblasts was not saturable, and the intracellular metronidazole concentrations increased linearly with the extracellular level. Temperature and pH had no significant influence on the uptake of metronidazole by fibroblasts. Probenecid and adenine had no influence on the uptake of metronidazole by fibroblasts. These findings indicate that metronidazole uptake does not involve a transporter. Metronidazole bound rapidly to human gingival fibroblasts, but the cell-associated drug declined progressively until it reached a stable plateau in 15 minutes.


CONCLUSIONS
Metronidazole rapidly entered human gingival fibroblasts via simple diffusion. Metronidazole easily reached the minimal inhibitory concentration in fibroblasts and gingiva. Given the fact that intracellular concentrations of metronidazole in other tissues and cells are also close to the plasma level, we speculate that metronidazole enters other tissues and cells via simple diffusion.
Yu
Liqiang
L
Dental Institute, General Hospital of the Chinese People's Liberation Army, Beijing, China.
Liu
Hongchen
H
E
Lingling
L
Wu
Xia
X
Wang
Dongsheng
D
D000225:Adenine / Q000494:pharmacology; D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D000293:Adolescent; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D045604:Extracellular Fluid / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005881:Gingiva / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008795:Metronidazole / Q000097:blood / Q000493:pharmacokinetics*; D008826:Microbial Sensitivity Tests; D011339:Probenecid / Q000494:pharmacology; D013696:Temperature; D013997:Time Factors
D000277:Adjuvants, Pharmaceutic; D000890:Anti-Infective Agents; D027682:Cation Transport Proteins; D049990:Membrane Transport Modulators; D008795:Metronidazole; D000225:Adenine; D011339:Probenecid