Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5636_Библиотеки_им_академика_М_И_Перельмана
.pdf
79
3 Fluorophotometry for Pharmacokinetic Assessment
https://t.me/med1917
Fig. 3.22 A fluorophotometer scan of a human subject is scanned for autofluorescent values in (a)
to be treated eye and (b) the contralateral untreated eye
application of 7% sodium fluorescein, the treated eye (Fig. 3.23a) corneal
fluorescence has risen without a change in the contralateral eye (Fig. 3.23b). The
distribution of fluorescein has not changed after 255 min (Fig. 3.24). Table 3.3 con-
tains a summary of the peak fluorescence values for the cornea and retina following
80
B.E. McCarey
https://t.me/med1917
Fig. 3.23 A fluorophotometer scan of a human subject is scanned 75 min after the topical
application of 7% sodium fluorescein (a). (b) The contralateral untreated eye
81
3 Fluorophotometry for Pharmacokinetic Assessment
https://t.me/med1917
Fig. 3.24 A fluorophotometer scan of a human subject is scanned 255 min after the topical
application of 7% sodium fluorescein (a). (b) The contralateral untreated eye
82
B.E. McCarey
Cornea Retina
Treatment
(ng/mL)
Contralateral
(ng/mL)
Treatment
(ng/mL)
Contralateral
(ng/mL)
Autofluorescence
14 11.1 6.0 4.8
Post-75
min 335 11.5 5.2 4.9
Post-255
min 191.9 15.5 8.2 4.0
https://t.me/med1917
Table 3.3 The peak fluorescein values as measure with the fluorophotometer
following topical application of fluorescein to the treated eye
topical applications of fluorescein. The experiment supports the difficulty of
delivering fluorescein to the posterior segment of the eye with topical corneal
applications.
References
Adler CA, Maurice DM, Paterson ME (1971) The effect of viscosity of the vehicle on the penetra-
tion of fluorescein into the human eye. Exp Eye Res 11:34–42
Araie M (1986) Carboxyfluorescein. A dye for evaluating the corneal endothelial barrier function
in vivo. Exp Eye Res 42:141–150
Araie M, Maurice D (1987) The rate of diffusion of fluorophores through the corneal epithelium
and stroma. Exp Eye Res 44:73–87
Berkowitz RA, Klyce SD, Salisbury JD, Kaufman HE (1981) Fluorophotometric determination of
the corneal epithelial barrier after penetrating keratoplasty. Am J Ophthalmol 92:332–335
Boets EP, van Best JA, Boot JP, Oosterhuis JA (1988) Corneal epithelial permeability and daily
contact lens wear as determined by fluorophotometry. Curr Eye Res 7:511–514
Bron AJ (1985) Prospects for the dry eye. Trans Am Ophthalmol Soc 104:801–811
Burstein NL (1980) Preservative cytotoxic threshold for benzalkonium chloride and chlorhexidine
in cat and rabbit corneas. Invest Ophthalmol Vis Sci 19:308–813
Burstein NL (1984) Preservative alteration of corneal permeability in humans and rabbits. Invest
Ophthalmol Vis Sci 25:1453–1457
Burstein NL, Klyce SD (1977) Electrophysiologic and morphologic effects of ophthalmic prepara-
tions on rabbit cornea epithelium. Invest Ophthalmol Vis Sci 16:899–911
Cadwallader DE, Ansel HC (1965) Hemolysis of erythrocytes by antibacterial preservatives. II.
Quarternary ammonium salts. J Pharm Sci 54:1010–1012
Champeau EJ, Edelhauser HF (1986) Effects of ophthalmic preservatives on the ocular surface:
conjunctiva and corneal uptake and distribution of benzalkonium chloride and chlorhexidine
digluconate. In: Holly FJ (ed) The preocular tear film: in health, disease, and contact lens wear.
Dry Eye Institute, Lubbock, TX, pp 292–302
Chang SW, Hu FR (1993) Changes in corneal autofluorescence and corneal epithelial barrier func-
tion with aging. Cornea 12:493–499
Chang SW, Hsu HC, Hu FR, Chen MS (1995) Corneal autofluorescence and epithelial barrier
function in diabetic patients. Ophthalmic Res 27:74–79
Cunha-Vaz J, de Abreu J, Campos A (1975) Early breakdown of the blood-retinal barrier in diabe-
tes. Br J Ophthalmol 59:649–656
de Kruijf EJ, Boot JP, Laterveer L, van Best JA, Ramselaar JA, Oosterhuis JA (1987) A simple method
for determination of corneal epithelial permeability in humans. Curr Eye Res 6:1327–1334
Forster S, Mead A, Sears M (1979) An interophthalmic communicating artery as explanation for
the consensual irritative response of the rabbit eye. Invest Ophthalmol Vis Sci 18:161–165
83
3 Fluorophotometry for Pharmacokinetic Assessment
https://t.me/med1917
Gobbels M, Spitznas M (1991) Effects of artificial tears on corneal epithelial permeability in dry
eyes. Graefes Arch Clin Exp Ophthalmol 229:345–349
Gobbels M, Spitznas M (1992) Corneal epithelial permeability of dry eyes before and after treat-
ment with artificial tears. Ophthalmology 99:873–878
Gobbels M, Spitznas M, Oldendoerp J (1989) Impairment of corneal epithelial barrier function in
diabetics. Graefes Arch Clin Exp Ophthalmol 227:142–144
Gobbles M, Spitznas M (1989) Influence of artificial tears on corneal epithelium in dry eye syn-
drome. Graefes Arch Clin Exp Ophthalmol 227:139–141
Gray JR, Mosier MA, Ishimoto BM (1985) Optimized protocol for Fluorotron Master. Graefes
Arch Clin Exp Ophthalmol 222:225–229
Grimes PA, Stone RA, Laties AM, Li W (1982) Carboxyfluorescein. A probe of the blood ocular
barriers with lower membrane permeability than fluorescein. Arch Ophthalmol 100:635–639
Hughes L, Maurice D (1984) A fresh look at iontophoresis. Arch Ophthalmol 102:1825–1829
Jones RF, Maurice DM (1966) New methods of measuring the rate of aqueous flow on man with
fluorescein. Exp Eye Res 5:208–220
Joshi A, Maurice D, Paugh JR (1996) A new method for determining corneal epithelial barrier to
fluorescein in humans. Invest Ophthalmol Vis Sci 37:1008–1016
Kanno Y, Loewenstein WR (1964) Intercellular diffusion. Science 143:959–960
Kuppens EVM, Stolwijk TR, de Keizer RJW, van Best JA (1992) Basal tear turnover and topical
timolol in glaucoma patients and healthy controls by fluorophotometry. Invest Ophthalmol Vis
Sci 33:3442–3448
Kuppens E, Stolwijk T, van Best J, de Keizer R (1994) Topical timolol, corneal epithelial perme-
ability and autofluorescence in glaucoma by fluorophotometry. Graefes Arch Clin Exp
Ophthalmol 232:215–220
Lin MC, Graham AD, Fusaro RE, Polse KA (2002) Impact of rigid gas-permeable contact lens
extended wear on corneal epithelial barrier function. Invest Ophthalmol Vis Sci
43:1019–1024
Maurice D (1963) A new objective fluorophotometer. Exp Eye Res 2:33–38
McCarey BE, al Reaves T (1995) Noninvasive measurement of corneal epithelial permeability.
Curr Eye Res 14:505–510
McCarey BE, Reaves TA (1997) Effect of tear lubricating solutions on in
permeability. Curr Eye Res 16:44–50
McCarey BE, Walter JJ (1998) Ocular fluorophotometry of fluorescein uptake following perior-
bital injections. Invest Ophthalmol Vis Sci 39:S275
McNamara NA, Fusaro RE, Brand RJ, Polse KA, Srinivas SP (1997) Measurement of corneal
epithelial permeability to fluorescein. A repeatability study. Invest Ophthalmol Vis Sci
38:1830–1839
McNamara NA, Polse KA, Bonanno JA (1998) Fluorophotometry in contact lens research: the
next step. Optom Vis Sci 75:316–322
Mishima S, Maurice DM (1971) In vivo determination of the endothelial permeability to fluores-
cein. Acta Soc Ophthalmol 75:236–243
Nelson JD (1995) Simultaneous evaluation of tear turnover and corneal epithelial permeability by
fluorophotometry in normal subjects and patients with keratoconjunctivitis sicca (KCS). Trans
Am Ophthalmol Soc 93:709–753
Occhipiniti JR, Mosier MA, La Motte J, Monji GT (1988) Fluorophotometric measurement of
human tear turnover rate. Curr Eye Res 7:995–1000
OcuMetrics I (1995) FM-2 Fluorotron™ Master, Operators Manual, OcuMetrics, Inc., 2224-C Old
Middlefield Way, Mountain View, CA 94043-2421, 650:960–3955
Ota Y, Mishima S, Maurice DM (1974) Endothelial permeability of the living cornea to fluores-
cein. Invest Ophthalmol Vis Sci 13:945–949
Paugh JR, Joshi A (1992) Novel fluorophotometric methods to evaluate tear flow dynamics in man.
Invest Ophthalmol Vis Sci 33:S950
Paugh JR, Saai A, Abhay J (1998) Preservative effect on epithelial barrier function measured with
a novel technique. Adv Exp Med Biol 438:731–735
vivo corneal epithelial
84 B.E. McCarey
https://t.me/med1917
Pfister RR, Burstein NL (1976) The effects of ophthalmic drugs, vehicles, and preservatives on corneal
epithelium: a scanning electron microscope study. Invest Ophthalmol Vis Sci 15:246–259
Ramselaar JA, Boot JP, van Haeringen NJ, van Best JA, Oosterhuis JA (1988) Corneal epithelial
permeability after instillation of ophthalmic solutions containing local anesthetics and preser-
vatives. Curr Eye Res 7:947–950
Schalnus R, Ohrloff C (1990) Permeability of the limiting cell layers of the cornea in
Eye Toxic Res 7:371–384
Tognetto D, Cecchini P, Sanguinetti G, Pedio M, Ravalico G (2001) Comparative evaluation of
corneal epithelial permeability after the use of diclofenac 0.1% and flurbiprofen 0.03% after
phacoemulsification. J Cataract Refract Surg 27:1392–1396
Tsuboti S, Pedersen JE (1987) Acetazolamide effect on the inward permeability of the blood-retina
barrier in diabetes. Invest Ophthalmol Vis Sci 28:92–95
van Best J, Tijin A, Tsoi EWSJ, Boets EP, Oosterhuis JA (1985) In vivo assessment of lens trans-
mission for blue-green light by autofluorescence measurement. Ophthalmic Res 17:90–95
van Best JA, Kappelhof JP, Laterveer L, Oosterhuis JA (1987) Blood aqueous barrier permeability
verses age by fluorophotometry. Curr Eye Res 6:855–863
van Zutphen H, Demel RA, Norman AW, van Deenen LLM (1971) The action of polyene antibiot-
ics on lipid bilayer membranes in the presence of several cations and anions. Biochim Biophys
Acta 241:310–330
Webber W, Jones DP, Wright P (1987) Fluorophotometric measurements of tear turnover rate in
normal healthy persons: evidence for a circadian rhythm. Eye 1:615–620
Yokoi K, Yokoi N, Kinoshita S (1998) Impairment of ocular surface epithelium barrier function in
patients with atopic dermatitis. Br J Ophthalmol 82:797–800
Zeimer RC, Cunha-Vaz JG, Johnson ME (1982) Studies on the technique of vitreous fluoropho-
tometry. Invest Ophthalmol Vis Sci 22:668–674
vivo. Lens
Chapter 4
https://t.me/med1917
Systemic Route for Retinal Drug Delivery:
Role of the Blood-Retinal Barrier
Masanori Tachikawa, Vadivel Ganapathy, and Ken-ichi Hosoya
Abstract Systemic delivery of therapeutic drugs to the retina is hindered by the
presence of the blood-retinal barrier (BRB) which consists of retinal vascular
endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB).
Recent progress in the BRB research has revealed that the BRB expresses a wide
variety of transporters essential for the blood-to-retinal influx transport of nutrients
and their analogs. At the same time, the BRB also possesses several transporters
responsible for the retina-to-blood efflux transport of xenobiotics and drugs, thus
being involved in the removal of potentially harmful compounds from the retina.
This information can be exploited to our advantage to establish efficient strategies
for optimal delivery of clinically relevant therapeutic drugs into the retina.
Abbreviations
ABC ATP-binding cassette
AZT 3¢-azido-3¢-deoxythymidine (zidovudine)
BAPSG N-4-benzoylaminophenylsulfonylglycine
BCRP Breast cancer resistance protein
BRB Blood-retinal barrier
CRT Creatine transporter
DHA Dehydroascorbic acid
ENT Equilibrative nucleoside transporter
GLUT Facilitative glucose transporter
HDL High-density lipoprotein
K.-i. Hosoya (*)
Department of Pharmaceutics, Graduate School of Medicine
and Pharmaceutical Sciences, University of Toyama,
Toyama 930-0194, Japan
e-mail: hosoyak@pha.u-toyama.ac.jp
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_4,
© American Association of Pharmaceutical Scientists, 2011
85
86
M. Tachikawa et al.
https://t.me/med1917
HIV Human immunodeficiency virus
LAT L (Leucine-referring)-type amino acid transporter
L-DOPA (-)-3-(3,4-dihydroxyphenyl)-L-alanine
MCT H+-coupled monocarboxylate transporter
6-MP 6-mercaptopurine
MRP Multidrug resistance-associated protein
MTF N5-methyltetrahydrofolate
OAT Organic anion transporter
OATP Organic anion transporting polypeptide
OCT Organic cation transporter
PAH p-aminohippuric acid
PCFT H+-coupled folate transporter
PCG Benzylpenicillin
PEPT H+-coupled peptide transporter
P-gp P-glycoprotein
RFC1 Reduced folate carrier
RPE Retinal pigment epithelial cells
RVEC Retinal vascular endothelial cells
SLC Solute carrier
SMCT Na+-coupled monocarboxylate transporter
SOPT Na+-coupled oligopeptide transporter
SR-BI Scavenger receptor class B type I
SVCT Na+-dependent vitamin C transporter
TAUT Taurine transporter
TR-iBRB Conditionally immortalized rat retinal capillary endothelial cell line
xCT Cystine/glutamate transporter
4.1 Introduction
Retinal diseases such as age-related macular degeneration, diabetic retinopathy, and
glaucoma have become an important therapeutic target with urgent medical needs.
Although the ophthalmic drug market is dominated by topical eye drop formulations for anterior segment drug therapies (Del Amo and Urtti 2008), development of
systemic drug delivery to the retina poses various hurdles in the treatment of retinal
diseases. In general, the restricted drug penetration rate from the circulating blood
to the retina is a major problem for retinal drug therapies. The retina is protected by
the blood-retinal barrier (BRB; Fig. 4.1) from potentially harmful compounds that
are present in the systemic circulation and produced in the retina. Although this role
of the BRB is certainly beneficial to the retina, it also reduces the efficacy in the retinal drug delivery via systemic administration. However, it has become increasingly
clear in recent years that the BRB performs the vectorial transfer of nutrients in the
blood-to-retina direction and also eliminates metabolic waste products in the retinato-blood direction (Hosoya and Tachikawa 2009). Such information would be useful
87
4 Systemic Route for Retinal Drug Delivery: Role of the Blood-Retinal Barrier
https://t.me/med1917
Fig. 4.1 Schematic representation of transport systems at the inner and outer blood-retinal barrier
(BRB). The BRB consist of complex tight junctions of retinal capillary endothelial cells (inner
BRB) and retinal pigment epithelial cells (outer BRB). The transport systems at the BRB can be
classified into three categories; (1) blood-to-retina influx transport processes, (2) efflux pumps, and
(3) retina-to-blood efflux transport processes. In secondary active transport, the abluminal/apical
transporters in the blood-to-retina influx transport process and the luminal/basolateral transporters
in the retina-to-blood efflux transport process, which are indicated by a question mark, are not well
characterized. GLUT facilitative glucose transporter; LAT L-type amino acid transporter; MCT H
coupled monocarboxylate transporter; SMCT Na
P-glycoprotein; MRP multidrug resistance-associated protein; BCRP breast cancer resistance
protein; Oat organic anion transporter; Oatp organic anion transporting polypeptide
+
-coupled monocarboxylate transporter; P-gp
+
-
to develop the systemic route for efficient retinal drug delivery. In this chapter, we
present a potential approach of the BRB-targeted retinal drug delivery through an
overview of transport systems that are expressed at the BRB.
4.1.1 Role of the Blood-Retinal Barrier as a Dynamic Interface
The BRB consists of retinal vascular endothelial cells (RVEC: inner BRB) and
retinal pigment epithelial (RPE) cells (outer BRB) (Fig. 4.1). The inner BRB is
responsible for nourishment of the inner two-thirds of the retina whereas the
outer BRB is responsible for nourishment of the remaining one-third of the retina
88
M. Tachikawa et al.
https://t.me/med1917
(Hosoya and Tomi 2005). Essential nutrients for neuronal cells, e.g., ganglion
cells, bipolar cells, horizontal cells, amacrine cells, and Müller glial cells are
supplied mostly across the inner BRB whereas those for photoreceptor cells are
supplied across the outer BRB. RVEC and RPE cells form tight monolayers with
complex tight junctions which prevent or decrease nonspecific diffusion across the
monolayer. Both cell types are well polarized. The luminal plasma membrane of
RVEC is in contact with blood whereas the abluminal membrane faces the retina.
Similarly, the basolateral plasma membrane of the RPE cells is in contact with
choroidal blood and the apical membrane faces the retina. Thus, the concerted
actions of transporters which are localized in different membranes of RVEC
and RPE cells enable the vectorial transport of a variety of compounds in the
blood-to-retina and the retina-to-blood directions.
4.1.2 Potential Approach of Blood-Retinal Barrier-Targeted
Systemic Drug Delivery to the Retina
A number of parameters need to be considered for systemic drug delivery to the
retina: retinal blood flow, influx and efflux transport systems at the BRB, protein
binding in the blood, clearance from the blood, and activity of drug metabolizing
enzymes in peripheral tissues, blood, and at the BRB. Recent progress in the BRB
research has revealed that multiple transporters/receptors are expressed at the
BRB. This has opened the door to the development of the BRB-targeted drug
delivery to the retina because drug recognition by the BRB transporters/receptors
would greatly influence the disposition into the retina. Figure 4.1 illustrates three
kinds of transport systems at the BRB. One group represents the blood-to-retina
influx transport systems that supply nutrients such as glucose, amino acids, nucleosides, monocarboxylates, and vitamins to retinal cells. Some transporters transport not only their physiologic substrates but also therapeutic drugs that bear
structural resemblance to their physiological substrates. Designing amino acidmimetic drugs which are recognized by amino acid transporters at the BRB is a
promising approach to achieve retinal drug delivery. Thus, the influx transport
systems at the BRB may have potential as a drug delivery route for the treatment
of retinal diseases. The second group consists of the efflux pumps that prevent
entry of xenobiotics into the RVEC and RPE cells by pumping them out back into
the circulating blood. These efflux systems are located in the luminal and basolateral membranes of RVEC and RPE cells, respectively. Especially for hydrophobic
drugs that penetrate the barrier mostly by passive diffusion, we need to consider
that these efflux processes may contribute to the restricted distribution of drugs to
the retina. The third group represents the retina-to-blood efflux transport systems
that act to eliminate metabolites and neurotoxic compounds from the retina.
To
evaluate the ability of various pharmacologic agents to penetrate the BRB,
it would be necessary to consider the combined net result of two different
Соседние файлы в папке Библиотека им академика М.И. Перельмана