MINIREVIEW
`
`Nasal Drug Administration: Potential for
`Targeted Central Nervous System Delivery
`
`CANDACE L. GRAFF, GARY M. POLLACK
`
`Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill,
`North Carolina 27599 7360
`
`Received 28 April 2004; revised 14 July 2004; accepted 18 November 2004
`
`Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20318
`
`ABSTRACT: Nasal administration as a means of delivering therapeutic agents pre-
`ferentially to the brain has gained significant recent interest. While some substrates
`appear to be delivered directly to the brain via this route, the mechanisms governing
`overall brain uptake and exposure remain unclear. Some substrates utilize the olfactory
`nerve tract and gain direct access to the brain, thus bypassing the blood brain barrier
`(BBB). However, most agents of pharmacologic interest likely gain access to the brain via
`the olfactory epithelium, which represents a more direct route of uptake. While the
`traditional BBB is not present at the interface between nasal epithelium and brain,
`P-glycoprotein (and potentially other barrier transporters) is expressed at this interface.
`In addition, work in this laboratory has demonstrated that P-glycoprotein throughout
`the brain can be modulated with nasal administration of appropriate inhibitors.
`The potential for targeted central nervous system delivery via this route is discussed.
`ß 2005 Wiley Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1187 1195, 2005
`Keywords: Nasal delivery; central nervous system; brain; blood brain barrier
`
`Delivery of drugs to the central nervous system
`(CNS) remains a challenge in the development of
`efficacious agents for central targets, mainly due
`to the impenetrable nature of the blood–brain
`barrier (BBB). In general, the BBB limits sub-
`strate penetration based on several characteris-
`tics, including lipophilicity, molecular size, and
`specificity for a variety of ATP-dependent trans-
`port systems. Expression of efflux transporters
`[i.e., P-glycoprotein (P-gp)] in the endothelial cells
`that form the BBB limits the ability of many
`lipophilic compounds, including potential thera-
`peutic agents, to reach target sites in the CNS (for
`review, see Graff and Pollack1). Due to the critical
`importance of effective drug delivery to the brain, a
`
`Correspondence to: Gary M. Pollack (Telephone: (919) 962
`0055; Fax: (919) 966 0197; E mail: gary_pollack@unc.edu)
`
`Journal of Pharmaceutical Sciences, Vol. 94, 1187–1195 (2005)
`ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association
`
`number of approaches (e.g., utilizing prodrugs,2
`inhibiting efflux transporters,3 disrupting the
`endothelial tight junctions that, along with the
`cell membrane, form the physical barrier,4 and
`use of nasal administration5) have been evaluat-
`ed to minimize the effects of the BBB. The utility of
`the nasal route as a portal for preferential delivery
`of therapeutic agents to the brain is the focus of
`this mini-review.
`The concept of nasal administration providing
`a means to deliver drugs directly to the CNS by
`bypassing the BBB is not entirely appropriate in
`its argument. Although some drugs may be
`delivered directly to the brain parenchymal tissue
`via the nasal route, BBB transport proteins,
`including but perhaps not limited to P-gp, are
`operative at this site and serve to limit the ability
`of substrates to access the brain via this route.6
`Furthermore, co-administration of a P-gp inhibi-
`tor by nasal instillation eliminates the barrier
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`1187
`
`Insys Exhibit 2007
`CFAD v. Insys
`IPR2015-01797
`
`Page 1 of 9
`
`

`
`1188
`
`GRAFF AND POLLACK
`
`function of this efflux transporter, resulting in
`enhanced delivery of P-gp substrates to the brain.
`Therefore, CNS drug delivery via the nasal route
`appears to be faced with obstacles that are similar
`to brain delivery after systemic administration.
`However, there may be unique opportunities asso-
`ciated with the use of nasal delivery to enhance
`overall brain uptake and maximize central phar-
`macologic effects.
`
`Nasal Delivery
`
`A drug administered by the nasal route may enter
`into the blood of the general circulation, may
`permeate the brain directly, or in some cases may
`follow both pathways (Fig. 1). However, many of
`the factors controlling the drug flux through each
`of these pathways remain unclear. In general,
`there are three routes along which a drug admi-
`nistered into the nasal cavity may travel. These
`routes include (1) entry into the systemic circula-
`tion directly from the nasal mucosa, (2) entry into
`the olfactory bulb via axonal transport along
`neurons, and (3) direct entry into the brain. The
`evidence supporting the role of each of these
`routes for a variety of model substrates is sum-
`marized in Table 1. This table is not intended to
`be comprehensive in nature, but rather to high-
`light some of the solutes from various classes that
`have been shown to follow one or more of these
`pathways.
`A drug that enters into the systemic circulation
`must be absorbed through the nasal mucosa.
`The fraction of the administered dose absorbed
`by this route will depend on the contact time
`with, and the solubility and metabolic stability of
`the drug in, the mucus, as well as the rate of
`
`Figure 1. Scheme depicting the possible fate of a
`solute delivered nasally. Dashed lines (---) indicate
`limited substrate delivery via this route. Question
`marks indicate routes for which the exact pathway is
`unclear. Figure adapted from Illum.12
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`nasal mucus clearance.7 Administration via this
`route avoids hepatic/gastrointestinal first-pass
`effects, and therefore may provide extensive re-
`lative absorption for substrates that have poor oral
`bioavailability.8 This particular route does not
`present any advantage for the delivery of agents to
`the CNS per se, as the substrate must traverse the
`BBB from the systemic circulation after absorp-
`tion from the nasal mucosa.
`A drug may be carried along the olfactory
`neuron by intracellular axonal transport to the
`olfactory bulb. This olfactory nerve pathway would
`allow the drug to be taken up into the neuronal cell
`(located in the olfactory epithelium) by endocyto-
`sis, with subsequent transport into the CNS. This
`route appears to be utilized by some metals,9 as
`well as macromolecules, viruses,10 and particu-
`lates, including proteins,11 and represents the only
`path from the nose to the brain by which the BBB
`may be bypassed. Despite the ability of this route
`to deliver agents to the olfactory bulb, transport to
`CNS sites beyond the olfactory system is unclear.
`Furthermore, this route is slow, and therefore does
`not account for the rapid appearance of some
`solutes in the brain and/or CSF following nasal
`administration.12
`The mechanisms governing direct delivery of
`substrates to the brain (parenchymal tissue and/or
`CSF13) via the olfactory epithelium are not well
`understood. This pathway requires that the sub-
`strate enter the olfactory epithelium at a point
`other than the affector neuron.14 Subsequently, a
`solute may be able to diffuse into the CSF that
`surrounds the brain from the perineural space.
`While this means of entry is feasible, it likely is not
`a pharmacologically viable route. The diffusion of
`the drug through the CSF into brain tissue would
`be against the flow of CSF,15 and the diffusion path
`is long considering the rapid turnover of CSF.16
`This rapid CSF turnover will particularly affect
`larger molecules (>1000), whereas it likely will
`have less of an affect on smaller, highly diffusible
`molecules. Furthermore, while this pathway may
`constitute one route of entry into brain tissue,17
`it is not likely to be the primary direct route.
`Although measurable drug concentrations have
`been observed in CSF following nasal administra-
`tion (e.g., cephalexin,18 zidovudine19), the actual
`pathway has not been elucidated and the pharma-
`cologic consequences are not clear. There are both
`a physical and a biochemical barrier present
`between the CSF and the brain parenchyma, and
`thus the drug concentration(s) between the brain
`and CSF typically will not be equivalent.1 Clearly,
`
`Page 2 of 9
`
`

`
`Table 1. Transport Pathways Followed by Various Solutes Administered via the Nasal Route
`
`Solute
`
`Animal Model
`
`Type of
`Administration
`
`Pathway Followeda
`
`References
`
`NASAL DRUG ADMINISTRATION
`
`1189
`
`Rabbit
`Rat
`Rat
`Rat
`
`Rat
`Rat
`Rat
`
`Mouse
`Mouse
`
`Mouse
`Mouse
`
`Nasal inoculation
`Nasal drops
`
`Nasal inoculation
`Nasal drops
`
`Olfactory nerve
`Direct; systemic;
`olfactory nerve
`Olfactory nerve
`Direct
`
`Metals
`Aluminum
`Manganese
`Cadmium
`Nickel
`Antivirals/antibiotics
`Zidovudine
`Cephalexin
`Sulfonamides
`Viruses
`Hepatitis virus
`Herpes simplex
`encephalitis virus
`Rabies
`Pneumococci
`Other drugs
`Dopamine
`Mouse
`Nasal drops
`Direct; olfactory nerve
`Cocaine
`Rat
`Nasal perfusion
`Direct (?)
`aDirect: nasal cavity! olfactory epithelium! CNS; Olfactory nerve: nasal cavity! olfactory epithelium! olfactory nerve!
`olfactory bulb; CSF: nasal cavity! CSF; Systemic: nasal cavity! systemic circulation.
`
`Nasal infusion
`Inhalation
`Nasal infusion
`Nasal application
`
`Direct (?)
`Olfactory nerve
`Olfactory nerve
`Olfactory nerve
`
`Nasal suspension
`Nasal solution
`Nasal perfusion
`
`CSF; systemic
`CSF; systemic
`CSF; systemic
`
`43
`
`44
`
`9
`
`45
`
`19
`
`18
`
`46
`
`10
`
`47,48
`
`49
`
`50
`
`51
`
`15
`
`a comprehensive understanding of the mechan-
`isms governing this direct epithelial pathway is
`necessary in order to investigate the use of nasal
`administration as a practical means of delivering
`agents to the brain, and as such, this mini-review
`will focus on this route.
`
`olfactory perinueronal space, which appears to be
`continuous with a subarachnoid extension that
`surrounds the olfactory nerve as it penetrates the
`cribiform plate.23,24 For a more complete descrip-
`tion of the relevant anatomy of the olfactory
`region, please see the review by Illum.12
`
`Olfactory Epithelium
`
`The olfactory epithelium (also known as the olfac-
`tory mucosa) is located at the roof of the nasal
`cavity. The olfactory epithelium has a pseudos-
`tratified, columnar structure and is composed of
`three main cell types: receptor (or olfactory) cells,
`supporting cells, and basal cells. The olfactory
`receptor cells are elongated bipolar neurons that
`have cell bodies located at various depths within
`the epithelium, with one end in the nasal olfactory
`epithelium and the other end extending through
`the holes in the cribiform plate of the ethmoid
`bone, terminating in the olfactory bulb.20,21 The
`supporting cells are covered with microvilli and
`extend from the mucosal surface of the neuro-
`epithelium to the basal membrane.14 The basal
`cells are located at the basal surface of the neuro-
`epithelial layer and continue to differentiate to
`become new receptor cells.22 It has been sug-
`gested that there is free communication between
`the nasal submucosal interstitial space and the
`
`Evidence for Direct Nose-to-Brain Transport
`in Humans
`
`Only a few studies, utilizing pharmacologic effect
`as a surrogate for drug entry into the CNS,
`provide evidence for the transport of drugs from
`the nasal cavity to the CNS in humans. Overall,
`these studies seem to confirm observations in
`animal models. Pietrowsky et al.25 conducted a
`double-blind crossover study in 15 healthy adults
`who received either 20 IU of arginine-vasopressin
`(AVP) nasally or 1.5 IU AVP intravenously on
`three different occasions, with a saline solution
`as a control treatment. Event-related potentials
`(ERP, representing a measure of brain wave
`activity) were recorded while subjects performed
`an auditory attention task. Intranasal admi-
`nistration of AVP substantially increased a com-
`ponent of the ERP (P3), while there was no
`apparent increase after intravenous adminis-
`tration of AVP or nasal administration of saline.
`Moreover, plasma concentrations were higher
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`Page 3 of 9
`
`

`
`1190
`
`GRAFF AND POLLACK
`
`after i.v. administration of AVP as compared to
`nasal administration. This study provides func-
`tional evidence for increased delivery of AVP to
`the CNS via nasal as opposed to intravenous
`administration. Furthermore, the effect produced
`by nasal AVP was rapid, and therefore was at-
`tributed to a direct delivery of AVP to the CNS,
`although the exact pathway was not elucidated.
`It also has been reported that intranasal
`administration of angiotensin II (ANG II) resulted
`in direct CNS activity.26 In a balanced cross-over
`design, 12 healthy adults were treated with ANG
`II intravenously or intranasally (placebo was in-
`cluded as a control). For intravenous and intrana-
`sal administration, similar plasma concentrations
`of ANG II were obtained. While both routes of
`administration resulted in comparable acute
`increases in blood pressure, the pharmacodynamic
`profiles differed. After intravenous administra-
`tion, blood pressure remained elevated, whereas it
`returned to baseline after nasal administration. In
`addition,
`intranasal ANG II counteracted the
`decrease in norepinephrine circulating observed
`after intravenous administration of ANG II, and
`enhanced plasma concentrations of vasopressin.
`These responses were similar to the effects ob-
`served after an intracerebroventricular adminis-
`tration of ANG II in animals.
`A double-blind, within-subject crossover study
`was conducted in 18 healthy adults to investigate
`the effects of insulin (20 IU) delivered nasally.27
`In this study, auditory evoked potentials (AEP,
`representing a measure of cortical sensory pro-
`cessing) were recorded while the subjects per-
`formed a vigilance task (oddball paradigm). Blood
`glucose and serum insulin were not affected by
`nasal insulin, suggesting that systemic exposure
`was minimal. However, nasal insulin reduced the
`amplitudes of the two components of the AEP, and
`increased latency, when compared to placebo.
`These results suggest that nasally adminis-
`tered insulin is able to enter the brain directly from
`the nasal cavity. While there are receptors locat-
`ed within the olfactory bulb (mostly related to
`chemoreception), to exploit this route for a phar-
`macologic endpoint, the substrates must be able to
`reach the target receptors, which likely are located
`within the brain parenchyma. While these studies
`indicate that some compounds appear to elicit
`pharmacodynamic responses following nasal deli-
`very, the actual distribution of compounds follow-
`ing nasal administration is not well understood.
`Clearly, a more comprehensive understanding
`of this distribution is necessary, and could be
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`achieved via comprehensive kinetic analysis using
`tissue slices or microdissection, or by using non-
`invasive techniques such as PET imaging
`
`Common Features with the Blood–Brain Barrier
`
`The nasal cavity has many features in common
`with the BBB, including the presence of tight
`junctions and the expression of transport proteins
`and metabolic enzymes. Specifically, tight junc-
`tions are observed in both the nasal mucosa and
`the olfactory epithelium. There is significant ex-
`pression and activity of a series of cytochrome
`P450 (CYP) isoforms, including CYP1A2, 2A, 2B,
`2C, 2E, and 3A.28,29 In addition, a variety of other
`metabolic enzyme systems, including NADPH-
`cytochrome P450 reductase, epoxide hydrolase
`(EH), glucuronosyltransferase (UGT), and gluta-
`thione transferase (GST) have shown significant
`activity in the nasal cavity.30,31 Finally, both P-gp
`and multidrug resistance protein (MRP1) have
`been demonstrated in the nasal mucosa.32 The
`potential expression of, and the role of multidrug
`resistance-related transporters in, the olfactory
`epithelium was unclear until very recently. How-
`ever, P-gp has been shown to be expressed in to
`the olfactory epithelium and in the endothelial
`cells that line the murine olfactory bulb, as well as
`in excised bovine olfactory epithelium.33 The func-
`tional significance of the transporter at this site is
`the focus of continuing investigation.
`
`Problems with Studying Nasal Delivery
`
`As with any biomedical research area, many of the
`studies performed to date have examined nasal
`delivery by utilizing rodent models. Species
`differences between these animals and humans
`in nasal and brain anatomy and physiology may
`confound the extrapolation of results to humans.
`In general, olfactory transport is expected to be
`more pronounced in rodents due to the anato-
`mical differences in the olfactory region between
`rodents and humans, as well as due to the
`experimental conditions utilized. Interspecies dif-
`ferences in nasal and brain anatomy and physiol-
`ogy must be considered before any assessment can
`be made regarding the utility of this method for
`drug delivery in humans. For instance, the olfac-
`tory bulb represents a relatively large portion
`of the CNS in rodents, and the nasal olfactory
`mucosa covers approximately 50% of the total
`nasal epithelium in rats and 45% in mice.34,35
`These structures are proportionately smaller in
`
`Page 4 of 9
`
`

`
`humans; the olfactory mucosa covers approximate-
`ly 5% of the total nasal epithelium in humans.34
`These anatomical differences may predispose the
`rat, more so than humans, to olfactory deposition
`and potential olfactory transport of some com-
`pounds, and suggest that this route of brain
`delivery may be less substantial in humans as
`compared to the rat. The CSF volume (160 mL in
`humans vs. 35 mL in mice) is replaced every 1.5 h
`in mice compared to every 5 h in humans, which
`may impact the interpretation of nose-to-brain
`drug delivery studies (particularly for larger
`molecules), especially those in experimental pro-
`tocols that utilize CSF concentrations as an in-
`dication of brain uptake.16,36 In addition, many
`experimental paradigms require that the animal
`be placed on its back to allow sufficient bathing
`of the olfactory area with a solution of the subs-
`trate of interest, which would likely enhance
`uptake. Additional research will be required to
`clarify the potential significance of the olfactory
`route of delivery of substrates to the brain in
`humans, and these limitations will need to be
`considered when interpreting the data collected
`from animals to date.
`
`Targeted CNS Delivery
`
`Several studies have been designed to examine
`the potential of the nasal route for enhancing
`the delivery of substrates to the brain. It has
`been proposed that nasal administration may
`allow a substrate to reach a target in the brain at
`a higher concentration than would be feasible
`with other routes of administration. For example,
`it was shown that [3H]-dopamine achieved a
`27-fold increase in olfactory bulb concentrations
`when administered nasally compared to sys-
`temic (intravenous) delivery.5,37 However,
`for
`most drugs studied to date, the overall amount
`detected in brain tissue is usually only 2%–3% of
`the administered dose after nasal instillation.
`Again, this highlights the need for a more com-
`prehensive understanding of the brain distribu-
`tion of compounds following nasal administration.
`For P-gp substrates, the amount of substrate
`delivered to brain tissue after nasal administra-
`tion was dependent on the presence of P-gp at the
`nose–brain barrier. In fact, the impact of P-gp on
`the brain uptake of nasally-administered sub-
`strates was similar to that for substrates admi-
`nistered systemically. Furthermore, it has been
`demonstrated that the effect of P-gp on the brain
`uptake of nasally-administered substrates can
`
`NASAL DRUG ADMINISTRATION
`
`1191
`
`be modulated by utilizing appropriate transport
`inhibitors.6 This observation led us to question
`whether nasal delivery could modulate the effect of
`P-gp on brain uptake only when the substrate was
`administered nasally, or whether the effect may
`be more generalized. In other words, could nasal
`delivery offer a means to target the BBB broadly
`but specifically, in apparent opposition to the pre-
`vailing hypothesis that nasal delivery serves to
`circumvent the BBB?
`
`Figure 2. Dose-response relationship for inhibition
`of P-gp-mediated efflux transport of 3H-verapamil
`by nasally administered rifampin. Symbols represent
`mean SD for n¼ 4 per rifampin dose; the fitted line
`represents a sigmoidal Hill equation. Panel (A) re-
`presents nasal 3H-verapamil administration and is
`characterized by Emax¼ 99 3%, ED50¼ 81 5 mM,
`g¼ 2.7 0.4 (parameter estimate standard error).
`Panel (B) represents systemic 3H-verapamil adminis-
`tration (i.v.) and is characterized by Emax¼ 61
`19%, ED50¼ 620 200 mM, g¼ 2.2 0.5 (parameter
`estimate standard error). Figures adapted from Graff
`and Pollack.6
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`Page 5 of 9
`
`

`
`1192
`
`GRAFF AND POLLACK
`
`In a series of experiments in this laboratory,
`nasal delivery of a P-gp inhibitor was demonstrat-
`ed to attenuate P-gp-mediated efflux of a substrate,
`regardless of the delivery route of the substrate
`(Fig. 2). Nasal administration of the model P-gp
`inhibitor rifampin enhanced uptake of the P-gp
`substrate [3H]-verapamil when [3H]-verapamil
`was administered nasally or systemically.
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`Despite the demonstration of enhanced sub-
`strate uptake, there was still an important ques-
`tion as to the pharmacologic relevance of P-gp
`inhibition by this route. If P-gp were inhibited only
`at the olfactory bulb, the utility of this method
`would be limited, since very few pharmacologic
`targets are located within the olfactory bulb
`itself. However, if nasally delivered inhibitors
`are able to inhibit BBB P-gp more universally,
`the utility of the method could be profound.
`A pharmacodynamic experiment exploring this
`question was performed utilizing systemically
`administered loperamide as a pharmacologically
`active P-gp probe (Fig. 3). This experiment de-
`monstrated that nasally delivered inhibitors
`appear to be able to modulate P-gp beyond the
`olfactory bulb. While peak antinociception achiev-
`ed utilizing nasal delivery of the inhibitor was
`somewhat lower than after systemic inhibitor
`delivery (8-fold increase following nasal admin-
`istration of the inhibitor compared to 12-fold
`increase following systemic administration), the
`inhibitor dose utilized was 125-fold lower for
`nasal as compared to systemic delivery (rifampin
`administration did not alter the systemic disposi-
`tion of loperamide). In addition, it appears that
`the overall exposure is similar regardless of de-
`livery route, as the area-under the effect-time
`curves are very similar. While there are opioid
`receptors located in the olfactory bulb, the degree
`of antinociception observed in these studies in-
`dicates that loperamide was able to penetrate to
`relevant pharmacologic targets. Loperamide is un-
`able to cross the BBB due to P-gp-mediated efflux.38
`
`Figure 3. Antinociception elicited by loperamide
`(10 mg/kg, s.c.) following nasal (1 mg/kg) or systemic
`(125 mg/kg,
`i.p.)
`rifampin administration. Panel
`(A) represents the maximum pharmacologic effect
`(represented as %ANE¼ [(observation-baseline)/base-
`line] * 100) achieved in each treatment group. Closed
`bars represent rifampin-treated groups; open bars
`indicate vehicle-treated groups (mean S.D., n¼ 4).
`*p < 0.001 vs. vehicle; **p < 0.001 vs. nasal rifampin.
`Panel (B) represents the area under the effect vs. time
`curve for both treatment groups. Closed bars indicate
`rifampin-treated groups; open bars indicate vehicle-
`treated groups (mean S.D., n¼ 4). *p < 0.001 vs.
`vehicle. Panel (C) displays a typical time course for
`loperamide-associated antinociception after rifampin
`pretreatment. Triangles indicate systemic rifampin;
`circles indicate nasal rifampin. Closed symbols indicate
`rifampin treatment; open symbols indicate vehicle
`control.
`
`Page 6 of 9
`
`

`
`Therefore, it seems likely that the enhanced anti-
`nociception associated with nasal delivery of a
`P-gp inhibitor is due to increased brain uptake due
`to BBB P-gp inhibition.
`The limitations of CNS delivery presented by
`the BBB represent the rate-limiting step in CNS
`drug development, since >98% of all new candi-
`date drugs for the brain do not cross the BBB
`efficiently.39 The expression of P-gp in the
`endothelial cells that form the BBB limits the
`ability of many lipophilic compounds, including
`potential therapeutic agents, to reach pharmaco-
`logic targets in the CNS. While a comprehensive
`discussion of the implications of P-gp modulation
`are beyond the scope of this review, several rele-
`vant reviews have appeared in the literature.1,40–42
`It is clear that a method allowing selective in-
`hibition of P-gp at the BBB would provide a
`therapeutic benefit for a variety of compounds
`that otherwise are unable to attain sufficient con-
`centration in the brain parenchyma due to P-gp-
`mediated efflux. Thus, nasal delivery appears to
`offer a variety of opportunities for CNS delivery,
`including bypassing the BBB by utilizing the olfac-
`tory nerve tract and direct brain delivery via the
`olfactory epithelium. Further characterization
`and understanding of this direct route is needed
`and the potential for BBB transporter modulation
`(including duration) via this route needs to be
`elucidated.
`
`REFERENCES
`
`1. Graff CL, Pollack GM. 2004. Drug transport at the
`blood-brain barrier and the choroid plexus. Curr
`Drug Metab 5(1):95 108.
`2. Johnson MD, Chen J, Anderson BD. 2002. Inves-
`tigation of the mechanism of enhancement of
`central nervous system delivery of 20-beta-fluoro-
`20,30-dideoxyinosine via a blood-brain barrier ade-
`nosine deaminase-activated prodrug. Drug Metab
`Dispos 30(2):191 198.
`3. Savolainen J, Edwards JE, Morgan ME, McNa-
`mara PJ, Anderson BD. 2002. Effects of a P-
`glycoprotein inhibitor on brain and plasma con-
`centrations of anti-human immunodeficiency virus
`drugs administered in combination in rats. Drug
`Metab Dispos 30(5):479 482.
`4. Erdlenbruch B, Alipour M, Fricker G, Miller DS,
`Kugler W, Eibl H, Lakomek M. 2003. Alkylglycerol
`opening of the blood-brain barrier to small and
`large fluorescence markers in normal and C6
`glioma-bearing rats and isolated rat brain capil-
`laries. Br J Pharmacol 140(7):1201 1210.
`
`NASAL DRUG ADMINISTRATION
`
`1193
`
`5. Dahlin M, Bergman U, Jansson B, Bjork E,
`Brittebo E. 2000. Transfer of dopamine in the
`olfactory pathway following nasal administration
`in mice. Pharm Res 17(6):737 742.
`6. Graff CL, Pollack GM. 2003. P-glycoprotein attenu-
`ates brain uptake of substrates after nasal instilla-
`tion. Pharm Res 20(8):1225 1230.
`7. Minn A, Leclerc S, Heydel JM, Minn AL, Denizcot
`C, Cattarelli M, Netter P, Gradinaru D. 2002. Drug
`transport into the mammalian brain: The nasal
`pathway and its specific metabolic barrier. J Drug
`Target 10(4):285 296.
`8. Hussain AA, Kimura R, Huang CH. 1984. Nasal
`absorption of testosterone in rats. J Pharm Sci
`73(9):1300 1301.
`9. Evans J, Hastings L. 1992. Accumulation of Cd(II)
`in the CNS depending on the route of administra-
`tion: Intraperitoneal, intratracheal, or intranasal.
`Fundam Appl Toxicol 19(2):275 278.
`10. Perlman S, Sun N, Barnett EM. 1995. Spread of
`MHV-JHM from nasal cavity to white matter of
`spinal cord. Transneuronal movement and involve-
`ment of astrocytes. Adv Exp Med Biol 380:73 78.
`11. Thorne RG, Emory CR, Ala TA, Frey WH, II. 1995.
`Quantitative analysis of the olfactory pathway for
`drug delivery to the brain. Brain Res 692(1 2):
`278 282.
`12. Illum L. 2000. Transport of drugs from the nasal
`cavity to the central nervous system. Eur J Pharm
`Sci 11(1):1 18.
`13. Chow HH, Anavy N, Villalobos A. 2001. Direct
`nose-brain transport of benzoylecgonine following
`intranasal administration in rats. J Pharm Sci
`90(11):1729 1735.
`14. Mathison S, Nagilla R, Kompella UB. 1998. Nasal
`route for direct delivery of solutes to the central
`nervous system: Fact or fiction? J Drug Target
`5(6):415 441.
`15. Chow HS, Chen Z, Matsuura GT. 1999. Direct
`transport of cocaine from the nasal cavity to the
`brain following intranasal cocaine administration
`in rats. J Pharm Sci 88(8):754 758.
`16. Enting RH, Hoetelmans RM, Lange JM, Burger
`DM, Beijnen JH, Portegies P. 1998. Antiretroviral
`drugs and the central nervous system. Aids 12(15):
`1941 1955.
`17. Banks WA, During MJ, Niehoff ML. 2004.
`Brain uptake of the glucagon-like Peptide-1 anta-
`gonist exendin(9-39) after intranasal administra-
`tion. J Pharmacol Exp Ther 309(2):469 475.
`18. Sakane T, Akizuki M, Yamashita S, Nadai T,
`Hashida M, Sezaki H. 1991. The transport of a
`drug to the cerebrospinal fluid directly from the
`nasal cavity: The relation to the lipophilicity of
`the drug. Chem Pharm Bull (Tokyo) 39(9):2456
`2458.
`19. Seki T, Sato N, Hasegawa T, Kawaguchi T, Juni K.
`1994. Nasal absorption of zidovudine and its
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`Page 7 of 9
`
`

`
`1194
`
`GRAFF AND POLLACK
`
`transport to cerebrospinal fluid in rats. Biol Pharm
`Bull 17(8):1135 1137.
`20. Hilger OA. 1989. Applied anatomy and physiology
`of the nose. In: Adams GL, Boles LR, Hilger PA,
`editors. Boles’s Fundamentals of Otolaryngology,
`ed., Philadelphia: W.B. Saunders. pp 177 195.
`21. Nolte J. 1988. The human brain. ed., St. Louis: C.V.
`Mosby Co.
`22. Graziadei PPC, Monti-Graziadei GA. 1985. Neuro-
`genesis and plasticity of the olfactory sensory
`nurons. Ann NY Acad Sci 457:127 145.
`23. Jackson RT, Tigges J, Arnold W. 1979. Subarach-
`noid space of the CNS, nasal mucosa, and lympha-
`tic system. Arch Otolaryngol 105:180 184.
`24. Erlich SS, McComb JG, Hyman S, Weiss MH. 1986.
`Ultrastructural morphology of the olfactory path-
`way for cerebrospinal fluid drainage in the rabbit.
`J Neurosurg 64:466 473.
`25. Pietrowsky R, Struben C, Molle M, Fehm HL,
`Born J. 1996. Brain potential changes after intra-
`nasal vs.
`intravenous administration of vaso-
`pressin: Evidence for a direct nose-brain pathway
`for peptide effects in humans. Biol Psychiatry 39(5):
`332 340.
`26. Derad I, Willeke K, Pietrowsky R, Born J, Fehm
`HL. 1998. Intranasal angiotensin II directly influ-
`ences central nervous regulation of blood pressure.
`Am J Hypertens 11(8 Pt. 1):971 977.
`27. Kern W, Born J, Schreiber H, Fehm HL. 1999.
`Central nervous system effects of
`intranasally
`administered insulin during euglycemia in men.
`Diabetes 48(3):557 563.
`28. Gu J, Zhang QY, Genter MB, Lipinskas TW,
`Negishi M, Nebert DW, Ding X. 1998. Purification
`and characterization of heterologously expressed
`mouse CYP2A5 and CYP2G1: Role in metabolic
`activation of acetaminophen and 2,6-dichloroben-
`zonitrile in mouse olfactory mucosal microsomes.
`J Pharmacol Exp Ther 285(3):1287 1295.
`29. Giorgi M, Marini S, Longo V, Mazzaccaro A, Amato
`G, Gervasi PG. 2000. Cytochrome P450-dependent
`monooxygenase activities and their inducibility by
`classic P450 inducers in the liver, kidney, and nasal
`mucosa of male adult ring-necked pheasants.
`Toxicol Appl Pharmacol 167(3):237 245.
`30. Bond JA, Harkema JR, Russell VI. 1988. Regional
`distribution of xenobiotic metabolizing enzymes in
`respiratory airways of dogs. Drug Metab Dispos
`16(1):116 124.
`31. Gervasi PG, Longo V, Naldi F, Panattoni G,
`Ursino F. 1991. Xenobiotic-metabolizing enzymes
`in human respiratory nasal mucosa. Biochem
`Pharmacol 41(2):177 184.
`32. Wioland MA, Fleury-Feith J, Corlieu P, Commo F,
`Monceaux G, Lacau-St-Guily J, Bernaudin JF.
`2000. CFTR, MDR1, and MRP1 immunolocaliza-
`tion in normal human nasal respiratory mucosa.
`J Histochem Cytochem 48(9):1215 1222.
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005
`
`33. Kandimalla KK, Donovan MD. 2003. Carrier medi-
`ated transport of small molecules across bovine
`olfactory mucosa: Implications in nose to brain
`transport. AAPS Pharm Sci Vol. 5, No. 4, Abstract
`T3140.
`34. Gross EA, Swenberg JA, Fields S, Popp JA. 1982.
`Comparative morphometry of the nasal cavity in
`rats and mice. J Anat 135(Pt. 1):83 88.
`35. Schreider J. 1986. Comparative anatomy and
`function of the nasal passages. In: Barrow CS,
`editor Toxicology of
`the nasal passages, ed.,
`Washington: Hemisphere Publishing Corporation.
`pp 1 25.
`36. Davson H, Welch K, Segal MB. 1987. Secretion of
`cerebrospinal fluid. The Physiology and Patho-
`physiology of the Cerebrospinal Fluid, ed., London:
`Churchill Livingstone. p 201.
`37. Dahlin M, Jansson B, Bjork E, Bergman U,
`Brittebo E. 2001. Levels of dopamine in blood and
`brain following nasal administration to rats. Eur J
`Pharm Sci 14(1):75 80.
`38. Dagenais C, Graff CL, Pollack GM. 2004. Variable
`modulation of opioid brain uptake by P-glyco-
`protein in mice. Biochem Pharmacol 67(2):269
`276.
`39. Terasaki T, Pardridge WM. 2000. Targeted drug
`delivery to the brain (blood-brain barrier, efflux,
`endothelium, biological transport). J Drug Target
`8(6):353 355.
`40. Matheny CJ, Lamb MW, Brouwer KR, Pollack GM.
`2001. Pharmacokinetic and pharmacodynamic
`implications of