Potential pharmacokinetic role of organic cation transporters in modulating the transcorneal penetration of its substrates administered topically.

PURPOSE: We hypothesize organic cation transporters (OCT) may have a potential role in determining the pharmacokinetics and toxicity of organic cation drugs applied topically. Hence, in the present in vivo study, we attempted to evaluate the role of OCT in modulating the transport of its substrates after topical application. METHODS: New Zealand albino rabbits of either sex were used. Transcorneal penetration of OCT substrates tetraethylammonium and metformin after single instillation was evaluated in the absence and presence of OCT blockers (quinidine and atropine). Aqueous humor (AH) samples were collected through paracentesis amounting to 70-100 µl under topical anesthesia at various time intervals. The samples were subjected for estimation of both substrate as well as blocker concentrations using liquid chromatography mass spectrometry. RESULTS: Topical pre-treatment (30 min before substrate) of OCT blockers significantly decreased the transcorneal penetration of OCT substrates after single topical administration. The levels of blockers reaching AH in the presence of substrates were also modulated at 60 min after its administration as compared with its control. CONCLUSION: OCT are functionally active in the uptake of their substrates from tear to AH. Therefore, OCT in the corneal epithelium may be positioned from apical to basolateral. When administering their substrates/blockers topically, both may be competing for OCT for their uptake across the cornea, thereby decreasing the corneal penetration. Hence OCT can have a potential pharmacokinetic role in modulating the ocular bioavailability of their substrates administered topically, which are used as ocular therapeutics.

Multidrug and toxin extrusion family SLC47: physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K.

The kidney plays an important role in the secretion of organic compounds including drugs, toxins and endogeneous metabolites. The renal elimination process of organic cations is mediated by two distinct transport systems expressed on the apical and basolateral membrane of proximal epithelial cells. In 2005, mammalian multidrug and toxin extrusion 1 (MATE1)/SLC47A1 was identified as an orthologue of bacterial NorM. MATE1 is the H(+)/organic cation antiporter at the apical membrane, which mediates the secretion of organic cations. Kidney-specific MATE2-K was isolated from human kidney and localized at the brush-border membrane of proximal tubules. Like MATE1, MATE2-K mediates the secretion of organic cations into urine. MATE1 and MATE2-K are involved in the excretion of important medications and the disruption of these transporters can cause severe pharmacological problems. Recent findings regarding the MATE/SLC47 family are summarized in this review.

Drug uptake systems in liver and kidney: a historic perspective.

Drugs and their metabolites are eliminated mainly by excretion into urine and bile. Studies in whole animals, isolated organs, cells, and membrane vesicles led to the conclusion that different transport systems are responsible for the transport of different classes of organic compounds (small, large, anionic, and cationic). In the early 1990s, functional expression cloning resulted in the identification of the first transporters for organic anions and cations. Eventually, all the major transport systems involved in the uptake of these organic compounds were cloned and characterized, and we now know that they belong to the organic anion transporters (OATs) and organic cation transporters (OCTs) of the SLC22A superfamily and the organic anion-transporting polypeptides (OATPs) of the SLCO superfamily of polyspecific drug transporters. Today we can explain, at the molecular level, why small and hydrophilic organic compounds are excreted predominantly through urine whereas large and amphipathic compounds are excreted mainly through bile, and we can start to predict drug-drug interactions in the case of new compounds.

Hepatobiliary excretion of berberine.

Berberine is a bioactive herbal ingredient isolated from the roots and bark of Berberis aristata or Coptis chinensis. To investigate the detailed pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion, an in vivo microdialysis coupled with high-performance liquid chromatography was performed. In the control group, rats received berberine alone; in the drug-treated group, 10 min before berberine administration, the rats were injected with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor; quinidine, both organic cation transport (OCT) and P-gp inhibitors; SKF-525A (proadifen), a cytochrome P450 inhibitor; and probenecid to inhibit the glucuronidation. The results indicate that berberine displays a linear pharmacokinetic phenomenon in the dosage range from 10 to 20 mg kg(-1), since a proportional increase in the area under the concentration-time curve (AUC) of berberine was observed in this dosage range. Moreover, berberine was processed through hepatobiliary excretion against a concentration gradient based on the bile-to-blood distribution ratio (AUC(bile)/AUC(blood)); the active berberine efflux might be affected by P-gp and OCT since coadministration of berberine and CsA or quinidine at the same dosage of 10 mg kg(-1) significantly decreased the berberine amount in bile. In addition, berberine was metabolized in the liver with phase I demethylation and phase II glucuronidation, as identified by liquid chromatography/tandem mass spectrometry. Also, the phase I metabolism of berberine was partially reduced by SKF-525A treatment, but the phase II glucuronidation of berberine was not obviously affected by probenecid under the present study design.