Comparative assessment of ocular tissue distribution of drug-related radioactivity after chronic oral administration of 14C-levofloxacin and 14C-chloroquine in pigmented rats

Fluoroquinolones have been reported to have a high affinity for melanin. The ocular tissue distribution and accumulation of radioactivity was compared after repeated oral administration of 14C-levofloxacin and 14C-chloroquine at daily doses of 20 mg (0.054 mmol) kg(-1) and 28 mg (0.054 mmol) kg(-1), respectively, in pigmented rats for 84 days. The mean serum level at 24 h following each dose of 14C-levofloxacin was almost constant in the range of 0.33-0.45 nmol equiv mL(-1) after the 14th dose and thereafter. The melanin-containing ocular tissues, such as iris ciliary body and stratum pigment chorioides sclera, showed a much higher concentration of radioactivity than other non-pigmented ocular tissues. The respective concentration in iris ciliary body and stratum pigment chorioides sclera after the 1st dose was 126.47 and 74.91 nmol equiv g(-1), and gradually increased with increasing dose number, reaching 1261.81 and 447.45 nmol equiv g(-1) after the 84th dose, which was ca. 10 and 6 times higher, respectively, than after the 1st dose. The mean serum level following each dose of 14C-chloroquine was almost constant in the range 0.51-0.87 nmol equiv mL(-1) after the 7th dose and thereafter. The respective concentration in iris ciliary body and stratum pigment chorioides sclera after the 1st dose was 572.10 and 709.41 nmol equiv g(-1), and gradually increased with increasing dose number, reaching 33 317.92 and 12 322.90 nmol equiv g(-1) after the 84th dose, which was ca. 58 and 17 times higher, respectively, than after the 1st dose. The concentration in aqueous humour, cornea, lens, vitreous body and retina after the 84th dose was 1.84, 6.33, 0.48, 5.60 and 11.42 nmol equiv g(-1) for 14C-levofloxacin and 18.84, 264.99, 27.26, 158.43 and 1020.89 nmol equiv g(-1) for 14C-chloroquine (ca. 10, 42, 57, 28 and 89 times higher, respectively, than for 14C-levofloxacin). Especially, the concentration in the retina was markedly higher after 14C-chloroquine administration than after 14C-levofloxacin administration. The concentration and the extent of accumulation of radioactivity not only in melanin-containing ocular tissues but also in other non-pigmented ocular tissues, such as retina, after chronic oral administration of 14C-levofloxacin once daily for 84 days were much lower than those after multiple dosing with 14C-chloroquine under the same conditions. These results indicate that levofloxacin would have a much lower risk for ocular toxicity than chloroquine after chronic dosing.