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To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges.

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the β-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-48)) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [(3)H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion-transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (K(m)) = 84.3 μmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC(50) = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine.

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The effects of green tea catechins on the main drug-metabolizing enzymatic system, cytochrome P450 (CYP), have not been fully elucidated. The objective of the present study was to evaluate the effects of green tea extract (GTE, total catechins 86.5%, w/w) and (-)-epigallocatechin-3-gallate (EGCG) on the activities of CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A in vitro, using pooled human liver and intestinal microsomes. Bupropion hydroxylation, amodiaquine N-deethylation, (S)-mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation and midazolam 1'-hydroxylation were assessed in the presence or absence of various concentrations of GTE and EGCG to test their effects on CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A activities, respectively. Each metabolite was quantified using UPLC/ESI-MS, and the inhibition kinetics of GTE and EGCG on CYP enzymes was analyzed. In human liver microsomes, IC50 values of GTE were 5.9, 4.5, 48.7, 25.1 and 13.8 µg/mL, for CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A, respectively. ECGC also inhibited these CYP isoforms with properties similar to those of GTE, and produced competitive inhibitions against CYP2B6 and CYP2C8, and noncompetitive inhibition against CYP3A. In human intestinal microsomes, IC50 values of GTE and EGCG for CYP3A were 18.4 µg/mL and 31.1 µM, respectively. EGCG moderately inhibited CYP3A activity in a noncompetitive manner. These results suggest that green tea catechins cause clinically relevant interactions with substrates for CYP2B6 and CYP2C8 in addition to CYP3A.

We have previously demonstrated that in mice, the decrease in serum thyroxine (T(4)) level by polychlorinated biphenyls (PCBs) occurs without an increase in the UDP-glucuronosyltransferase (T(4)-UDP-GT) for T(4) glucuronidation, although the PCB-induced decrease in rats is generally thought to occur through induction of T(4)-UDP-GT, UGT1A1, and UGT1A6. In the present study, to further clarify the relationship between the decrease in serum T(4) level and the increase in UGT1A activity by PCB in rats, we examined the relationship using Wistar rats and Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. The serum total T(4) level was markedly decreased not only in the Wistar rats but also in the Gunn rats 4 days after treatment with a PCB, Kanechlor-500 (KC500, 100 mg/kg) or 2,2',4,5,5'-pentachlorobiphenyl (PentaCB, 112 mg/kg), and there was no significant difference in magnitude of the decrease between the two rat strains. At the same time, the level and activity of T(4)-UDP-GT were significantly increased by treatment with either KC500 or PentaCB in Wistar rats but not in Gunn rats. In addition, no significant change in the level of serum total triiodothyronine (T(3)) and thyroid-stimulating hormone by the KC500 treatment was observed in either Wistar or Gunn rats. Furthermore, significant decrease in the activity of hepatic type-I deiodinase, which mediates the deiodization of T(4) and T(3), by treatment with KC500 or PentaCB was observed in both Wistar and Gunn rats. From the serum of KC500- or PentaCB-treated Wistar and Gunn rats, mono- and di-hydroxylated PCB metabolites, which would bind to T(4) binding serum protein (transthyretin), were detected. In conclusion, the present results suggest that the decrease in serum total T(4) level by either KC500 or PentaCB in Gunn rats was not dependent on the increase in hepatic T(4)-UDP-GT activity. The findings further suggest that the PCB-mediated decrease in serum T(4) level might occur, at least in part, through formation of the hydroxylated PCB metabolites. Furthermore, even in Wistar rats, the PCB-mediated decrease in serum T(4) level might occur not only through the increase in hepatic T(4)-UDP-GT but also via formation of hydroxylated PCB metabolites.