[Ocular penetration and pharmacokinetics of topical voriconazole in rabbit eyes].
OBJECTIVE
To investigate the penetration of topical 1% voriconazole into the cornea and aqueous humor in New Zealand white rabbits.


METHODS
It was a experimental study. Forty-eight healthy rabbits were randomly divided into groups A (21 cases), B (21 cases) and C (6 cases). Blank samples from group C were used to determine the essential parameters for the validation of analytical procedures. A single 50 microl drop of 1% voriconazole was administered in group A (non-debrided cornea) and group B (debrided cornea). The aqueous humor and the cornea were obtained at 2, 5, 10, 15, 30, 60 and 90 min after application. All samples were analyzed by high-performance liquid chromatography (HPLC). The HPLC system consisted of Waters 1525 pump, Phenomenex Luna C18 (250.0 mm x 4.6 mm, 5.0 microm) column, Phenomenex C18 (4.0 mm x 3.0 mm, 5.0 microm) analytical steel column and a Waters Empower data workstation. The UV detector was set to 255.0 nm. Methanol-0.04 mol/L ammonium hydroxide (62:38, V/V) was used as mobile phase and the flow rate was 0.8 ml/min. External standard was used in this assay. The pharmacokinetic parameters were calculated with nonlinear least square method by the computer.


RESULTS
Calibration curves were linear over the range 0.1-15.0 mg/L. The concentration at 0.1 mg/L was the lowest quantified limit. The recovery of voriconazole from aqueous humor samples ranged from 91.06% to 94.80%, and ranged from 79.84% to 83.20% in the cornea samples. After single dose application, the drug concentration in aqueous humor peaked at 10 min in both group A [ (5.172 +/- 1.012) mg/L] and group B [(6.118 +/- 1.123) mg/L], and the parameters t(1/2 ke) in groups A and B were 6.859 min and 13.176 min, respectively. However, peak drug levels were achieved immediately at 2 min in the cornea [group A: (9.958 +/- 3.481) microg/g and group B: (158.476 +/- 10.462) microg/g]. The parameter t(1/2 beta) in nondebrided cornea was 94.938 min and 46.367 min in debrided corneas.


CONCLUSIONS
Topical voriconazole exhibits excellent penetration into the cornea, and effective high drug levels are achieved in both the cornea and aqueous humor after single dose application. It can be a prominent agent for the treatment of fungal keratitis in the future.
Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, China.
Ming-xia
MX
Sun
Jia-qi
JQ
Chen
Mei-cun
MC
Yao
Cheng-tian
CT
Ye
Jia
J
Li
Ming-ming
MM
Huang
D000287:Administration, Topical; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065819:Voriconazole
D009883:Ophthalmic Solutions; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole