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      Review of Intraocular Pharmacokinetics of Anti-Infectives Commonly Used in the Treatment of Infectious Endophthalmitis

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          Abstract

          Although intravitreal administration of anti-infectives represents the standard treatment for infectious endophthalmitis, the knowledge about their pharmacokinetics is still limited. In this review, we aimed to summarise the factors influencing the pharmacokinetics of the anti-infective agents. We have conducted a comprehensive review of the preclinical pharmacokinetic parameters obtained in different studies of intravitreal injections of anti-infectives performed on animals, mainly rabbits. The two aspects with the biggest influence on pharmacokinetics are the distribution in the vitreous humour and the elimination through the posterior segment. The distribution can be affected by the molecular weight of the drug, the convection flow of the vitreous, the condition of the vitreous humour depending on the age of the patient, the possible interactions between the drug and the components of the vitreous, and the presence of vitrectomy. Meanwhile, the elimination includes the metabolism of the drug, the clearance via the anterior and posterior routes, and the possible inflammation of the eye resulting from the disease. Understanding the pharmacokinetics of the anti-infectives used in clinical practice is essential for a correct application. The information provided in this review could offer guidance for selecting the best therapeutic option according to the characteristics of the drugs.

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          Most cited references 84

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          Pharmacokinetic aspects of retinal drug delivery

          Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.
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            Role of P-glycoprotein in pharmacokinetics: clinical implications.

            P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.
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              Drug transport in corneal epithelium and blood-retina barrier: emerging role of transporters in ocular pharmacokinetics.

              Corneal epithelium and blood-retina barrier (i.e. retinal capillaries and retinal pigment epithelium (RPE)) are the key membranes that regulate the access of xenobiotics into the ocular tissues. Corneal epithelium limits drug absorption from the lacrimal fluid into the anterior chamber after eyedrop administration, whereas blood-retina barrier restricts the entry of drugs from systemic circulation to the posterior eye segment. Like in general pharmacokinetics, the role of transporters has been considered to be quite limited as compared to the passive diffusion of drugs across the membranes. As the functional role of transporters is being revealed it has become evident that the transporters are widely important in pharmacokinetics. This review updates the current knowledge about the transporters in the corneal epithelium and blood-retina barrier and demonstrates that the information is far from complete. We also show that quite many ocular drugs are known to interact with transporters, but the studies about the expression and function of those transporters in the eye are still sparse. Therefore, the transporters probably have greater role in ocular pharmacokinetics than we currently realise.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                29 May 2018
                June 2018
                : 10
                : 2
                Affiliations
                [1 ]Department of Pharmacology, Pharmacy and Pharmaceutical Technology and Industrial Pharmacy Institute, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; andrealuaces21@ 123456gmail.com (A.L.-R.); Miguel.gonzalez.barcia@ 123456segas.es (M.G.-B.)
                [2 ]Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; Maria.Jesus.Lamas.Diaz@ 123456sergas.es
                [3 ]Pharmacy Department, Clinical University Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain
                [4 ]Ophthalmology Department, Clinical University Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain; mariajose.blanco@ 123456usc.es (M.J.B.-T.); mariagilmtez@ 123456hotmail.com (M.G.-M.); francisco.gonzalez@ 123456usc.es (F.G.); franciscogomez-ulla@ 123456institutogomez-ulla.es (F.G.-U.)
                [5 ]Department of Surgery and Medical-Surgical Specialties and CIMUS, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain
                Author notes
                [* ]Correspondence: francisco.otero@ 123456usc.es (F.-J.O.-E.); anxordes@ 123456gmail.com (A.F.-F.); Tel.: +34-609718821 (F.-J.O.-E.); +34-659695693 (A.F.-F.)
                Article
                pharmaceutics-10-00066
                10.3390/pharmaceutics10020066
                6027276
                29844284
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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