Drug Transporter Expression and Localization in Rat Nasal Respiratory and Olfactory Mucosa and Olfactory Bulb: Fig. 1.

Abstract

ABSTRACT:Uptake of drugs and other xenobiotics from the nasal cavity and into either the brain or systemic circulation can occur through several different mechanisms, including paracellular transport and movement along primary olfactory nerve axons, which extend from the nasal cavity to the olfactory bulb of the brain. The present study was conducted to expand knowledge on a third means of uptake, namely the expression of drug transporters in the rat nasal epithelium. We used branched DNA technology to compare the level of expression of nine transporters [(equilibrative nucleoside transporters (ENT)1 and ENT2; organic cation transporter (OCT)1, 2, and 3; OCTN1; organic anion-transporting polypeptide (OATP)3; and multidrug resistance (MRP)1 and MRP4] in nasal respiratory mucosa, olfactory mucosa, and olfactory bulb to the level of expression of these transporters in the liver and kidney. Transporters with high expression in the nasal respiratory mucosa or olfactory tissues were immunolocalized by immunohistochemistry. ENT1 and ENT2 expression was relatively high in nasal epithelia and olfactory bulb, which may explain the uptake of intranasally administered nucleoside derivatives observed by other investigators. OATP3 immunoreactivity was high in olfactory epithelium and olfactory nerve bundles, which suggests that substrates transported by OATP3 may be candidates for intranasal administration. IntroductionInterest is increasing in the use of the intranasal route for drug delivery. Although intranasal delivery avoids issues such as first-pass biotransformation by the liver after oral administration, there are significant hurdles such as bioavailability, degradation by nasal proteases, and an apparent size limitation for materials that can be delivered into the systemic circulation or the brain after intranasal administration. Delivery of intranasally administered drugs into either the brain or systemic circulation can occur by means of several processes. Expression of several metal transporters (DMT1, ZIP14) has been shown in rodent olfactory mucosa (Thompson et al., 2007;Genter et al., 2009), and transection of the olfactory nerve stopped the transport of manganese and thallium from the nasal cavity into the brain (Kinoshita et al., 2008). Furthermore, ipsilateral transsynaptic movement of manganese has been shown (Dorman et al., 2002). Movement of molecules between epithelial cells, i.e., paracellular transport, can be promoted by adjuvants such as poly-L-arginine that "loosen" the intercellular junctions that comprise the nasal bloodbrain barrier. An unfortunate side effect of some adjuvants is serious and potentially permanent damage to nasal tissues (Natsume et al., 1999). Finally, the nasal mucosa is highly vascularized, allowing drugs applied to the epithelial surface to be rapidly absorbed into the bloodstream (Türker et al., 2004).The delivery of nucleoside analogs such as zidovudine and 2Ј,3Ј-didehydro-3Ј-deoxythymidine to the cerebral spinal fluid (CSF) has been demonstrated after intranasal administra...

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

“…The pyrilamine transporter actively takes up oxycodone across the rat blood brain barrier and has been found in the nasal mucosa [28][29][30]. It is unknown if the pyrilamine transporter is present in humans and, if so, whether it is expressed in the salivary mucosal epithelium.…”

Microarray Determination of the Expression of Drug Transporters in Humans and Animal Species Used for the Investigation of Nasal Absorption

“…40, 41 Similarly, microarray analysis of OCT3 (SLC22A3) in the rat nasal mucosa revealed that it was moderately to highly expressed, which contradicted what was previously reported using branched DNA technology. 32 …”

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

“…Although, to our knowledge, this was the first time that IN GUO administration was investigated, the delivery of nucleoside analogs to the CNS has been demonstrated by several works through IN administration in rodents [34,35]. Indeed, nucleoside transporters were found in the nasal epithelia, pointing out that the uptake of GUO by their specific transporters can facilitate its delivery to the brain [36]. The pathway by which GUO applied to the nostril reaches the CNS seems to be reached as fast as only 5 min post-injection.…”