Pharmacokinetic Analysis of Intraocular Penetration of Latanoprost Solutions with Different Preservatives in Human Eyes.

PURPOSE: To investigate the effect of excipients on latanoprost penetration into the aqueous humor with clinically available 6 products with different solutions mainly in the types and concentrations of preservatives. METHODS: In 363 patients with cataracts, we instilled 1 latanoprost drop in 1 eye before surgery. The drop was randomly selected by brand name product (A) and 5 generic products (B-F) composed with different excipients. B contains similar excipients to A. C and D contain lower concentrations of benzalkonium chloride than A. E includes sodium benzoate, and F contains no preservatives. At 0.5-1, 3, and 6 h after instillation, samples of aqueous humor were collected to determine the latanoprost free acid by mass spectrometry. The time course of intraocular concentration and the areas under the aqueous humor latanoprost free acid concentration-time curves (AUCs) were calculated. RESULTS: At 0.5-1 h, the aqueous humor concentration of latanoprost free acid was 8.5 ± 1.0 ng/mL for C, which was significantly higher (P < 0.01) than that of A (3.4 ± 0.5 ng/mL). At 3 and 6 h, however, no significant difference was noted in the concentrations of latanoprost free acid between the brand name and generic products. For each of the generic products, the peak free acid concentration was above the known threshold concentration for biological activity. At 6 h postdose, however, the levels of latanoprost free acid were below the threshold for Products C, E, and F. Comparisons of AUC0-6h and AUC0-24h values showed that these parameters were the greatest with A, and E was significantly inferior to A (P < 0.05). CONCLUSIONS: Currently available latanoprost solutions with different preservatives showed sufficient intraocular concentration to activate the FP receptor, but different pharmacokinetic profiles of absorption or elimination.

Pharmaceutical studies of levothyroxine sodium hydrate suppository provided as a hospital preparation.

The levothyroxine sodium hydrate suppository (L-T4-suppository) is provided as a hospital preparation for the treatment of hypothyroid patients with dysphagia in Japan because only oral preparations of levothyroxine sodium (L-T4) are approved for the treatment of hypothyroidism. However, it has been found that serum thyroxine and triiodothyronine levels do not increase as expected with the hospital preparation, requiring a higher dosage of L-T4 in the L-T4-suppository than in the oral preparations. In this study, to determine an effective thyroid gland hormone-replacement therapy for patients with dysphagia, the pharmaceutical properties of the L-T4-suppository were investigated. Suppositories containing 300 µg L-T4 in a base of Witepsol H-15 and Witepsol E-75 (ratio of 1 : 1) were prepared according to Chiba University Hospital's protocol. Content uniformity, stability, and suppository release were tested. The L-T4-suppository had uniform weight and content. The content and release property were stable over 90 d when the L-T4-suppository was stored at 4 °C and protected from light. The release rate of L-T4 increased as pH increased. However, no L-T4 was released below pH 7.2. The release rate of L-T4 decreased as temperature decreased. These findings suggest that the low level of release of L-T4 in the rectum under physiological conditions may be the cause of the low serum thyroxine and triiodothyronine levels following L-T4-suppository administration.

Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes.

Using the Xenopus oocyte expression system, human Nramp2, a human intestinal iron transporter, was shown to work as a cadmium transporter. An 1824-bp human Nramp2 cDNA was constructed by PCR cloning from reverse transcription products of human kidney mRNA. When the pH of the extracellular solution was 6.0, human Nramp2 transported (109)Cd(2+). Substitution of external Cl(-) with NO3- had no effect on human Nramp2-dependent cadmium uptake. The concentration-dependent Cd(2+) transport of human Nramp2 indicated Michaelis-Menten type transport with an average K(m) value of 1.04 +/- 0.13 microM and an average V(max) of 14.7 +/- 1.9 pmol/oocyte/h (n = 3). Cd(2+) transport via human Nramp2 was inhibited significantly by Cd(2+), Fe(2+), Pb(2+), Mn(2+), Cu(2+), and Ni(2+), while it was not inhibited by Hg(2+) and Zn(2+). Transport of 0.1 microM Cd(2+) by human Nramp2 was inhibited by metallothionein (IC50 = 0.14 microM). Therefore, human Nramp2 is suggested to function as a pH-dependent cadmium absorption transporter on the luminal membrane of human intestinal cells.