Review ArticlePharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications
Introduction
It has been known for years that injecting a drug solution through the tympanic membrane into the middle ear allows the drug to reach and influence function of the inner ear (Ersner et al., 1951; Schuknecht, 1956). The field of local drug delivery to the ear took on greater relevance when in the mid-1990's local delivery of gentamicin became a widely-accepted clinical therapy for the treatment of Meniere's disease (Lange, 1989; Nedzelski et al., 1993; Toth and Parnes, 1995). Since that time, we have learned that the pharmacokinetics of the inner ear with locally-applied drugs is rather complex, involving the interaction of multiple elements. Some share similarities with other systems of the body, such as entry from the vasculature which has some similarities to that in the eye or the brain. Others, such as passage through the round window membrane, distribution through the different fluid and tissue compartments of the ear, and fluid exchange across the cochlear aqueduct, are unique to the ear. Here we review what we know so far about inner ear pharmacokinetics with a primary emphasis on drugs currently used in clinical practice.
The ear consists of a number of interconnected compartments that an applied drug can access.
- 1)
Middle ear. The middle ear is normally gas-filled but becomes a fluid-filled space communicating with perilymph when drug solution is applied there. The middle ear is lined with epithelium that on the ventral surface, leading to the Eustachian tube, is of endodermal origin and is densely ciliated. In contrast, dorsal surfaces of the epithelium and regions in the vicinity of the round window membrane and stapes are of neural crest origins and are not ciliated (Thompson and Tucker, 2013). The epithelium is both highly vascularized and includes lymphatic drainage to the retroauricular and junctional lymph nodes (Lim and Hussl, 1975). Fluid and/or drug loss through the Eustachian tube, via the vasculature and via the lymphatics can all contribute to the decline of middle ear concentration with time after drug application, as can fluid or mucus secretion by the epithelium. An initial breakdown (metabolism) of drugs in the middle ear also likely occurs but only limited quantitative data are yet available. The primary function of the middle ear epithelium is to maintain the normal gas-filled state and removal of applied drug solutions by these multiple processes occurs as a result of that specialization.
- 2)
Inner Ear. The inner ear comprises prominent fluid spaces containing endolymph or perilymph, but drugs entering the inner ear do not remain confined to just the fluid spaces. Most of the adjacent tissue spaces are not bounded by tissues with tight junctions so drugs rapidly equilibrate with the extracellular spaces of the spiral ligament, the organ of Corti, the spiral ganglion and of the auditory and vestibular nerves. Depending on permeability properties, drugs may enter the intracellular compartments of these tissues or become membrane-bound if lipophilic. Distribution between endolymph and perilymph depends on where the drug enters the ear, whether by systemic or local application, and whether the drug can pass through the tight, cellular endolymph-perilymph barrier. In the cochlea, distribution of charged molecules between endolymph and perilymph is also influenced by the endocochlear potential. Fluid spaces in the bone of the otic capsule also interact with perilymph, with incomplete bone-lining cells (Chole and Tinling, 1994) and a lacuno-canalicular system in the bone in open fluid communication with perilymph (Zehnder et al., 2005).
- 3)
Cranium. Perilymph is in open fluid communication with cerebrospinal fluid (CSF). The endolymphatic sac also contacts the dura mater in the posterior fossa. These communications raise the possibility that substances applied to perilymph may gain access to the brain. In rodents, where the cochlear aqueduct is relatively large, passage of drugs through the aqueduct is largely mitigated by the high rate of CSF turnover. While the CSF may be providing a sink to which perilymphatic drugs are lost (Salt et al., 2015), drug accumulation in CSF is generally low. Although in humans the aqueduct is longer and narrower, there are instances of hearing loss after intrathecal administration of ototoxic drug (Maarup et al., 2015). The passage of drugs from the ear to the brain via the auditory and vestibular nerves has also been proposed (Praetorius et al., 2007; Zhang et al., 2012).
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Vasculature. For the inner ear the vasculature represents a large sink to which drugs can be lost (or gained following systemic applications), impeded by the tight blood labyrinth barriers. This includes the blood-perilymph and blood-strial barriers which may have different characteristics. Each of the tissues of the middle and inner ear, including the bone of the otic capsule, has an associated vasculature that may contribute to the overall pharmacokinetics of the inner ear. It should also be borne in mind that any barrier is only as good as its weakest segment, with pharmacokinetics potentially influenced by local defects in the barrier.
A schematic of the main processes and compartments underlying inner ear pharmacokinetics with intratympanic drug applications is shown in Fig. 1. The figure shows a drug-containing formulation injected through the tympanic membrane into the middle ear cavity. Drug enters the inner ear through multiple pathways, including through the round window (RW) membrane and the stapes (King et al., 2011; Salt et al., 2012a). Drug is lost from the middle ear by multiple mechanisms, as discussed above. As the drug enters perilymph it initially distributes throughout the fluid and tissue spaces of basal turn and vestibule, with spread along the scalae towards the cochlear apex occurring more slowly. In the basal turn of ST, drug levels are diluted by CSF, either entering through the cochlear aqueduct as a volume flow, or as a CSF-perilymph exchange caused by pressure-induced fluid oscillations across the CA. Drug can be lost from the inner ear fluids by multiple processes, including uptake, buffering or binding to cellular or non-cellular components of the ear, or through elimination by the vasculature across the blood-labyrinth barriers.
Section snippets
Pharmacokinetics of the ear
Pharmacokinetics is the science of drug movements in the body, including absorption, distribution, metabolism, and excretion. In practice, however, all the applied drug may not be available so factors related to drug liberation are usually also considered, leading to the acronym LADME: Liberation, Absorption, Distribution, Metabolism and Elimination. In 2009, we first applied this concept to the ear (Salt and Plontke, 2009), providing a structured framework for systematically studying,
Molecular properties of drugs used in the ear
At present, only a small number of drugs are widely used in routine clinical practice for therapy of the ear. The aminoglycoside gentamicin is used to treat Meniere's disease (Lange, 1989; Nedzelski et al., 1993) and corticosteroids, mainly dexamethasone and methylprednisolone, are used to treat Meniere's disease, idiopathic sudden sensorineural hearing loss and other forms of acute hearing loss (Hamid and Trune, 2008). The different forms of these molecules that are used for therapy of the ear
Middle ear kinetics
When drug solution is injected into the middle ear it does not remain “undisturbed”, waiting for the dissolved drug to diffuse into the inner ear. As discussed earlier, the middle ear has a number of powerful mechanisms to remove fluids and drugs. For intratympanic applications in humans, the patient lies in a supine position for 20–30 min with the head orientated to keep the Eustachian tube uppermost, so that drug solution applied to the RW niche does not immediately drain towards the
Barriers of the ear
The main barriers to drug entry into the inner ear are formed by specialized cell layers, as reviewed elsewhere (Salt and Hirose, 2018). Endothelial cells of blood vessels provide the blood-perilymph and blood-strial barriers. They restrict the entry of systemically-applied drugs into the ear and control the elimination of locally-applied drugs. For drugs applied intratympanically, the primary barrier restricting passage into perilymph is the epithelium of the middle ear, which covers both the
Comparisons between drugs
The above analysis confirms that dexamethasone enters the ear far more readily than dexamethasone-phosphate, but can only be applied at low concentration due to its limited solubility. An important question is therefore which form of dexamethasone gives the highest perilymph concentration in absolute terms. The measured perilymph concentration, averaged across all 10 samples collected, was 2.18 μg/ml for dexamethasone (applied at a concentration of 94.2 μg/ml) and was 4.15 μg/ml for
Intratympanic applications
The amount and distribution of drug in perilymph depends both on the substance applied and on the application protocol. Based on the kinetic properties for the 3 drugs presented above we can calculate their likely distribution throughout the human inner ear for the application protocols typically used clinically, as shown in Fig. 8. This calculation assumes that pharmacokinetic properties derived from animal experiments are comparable to those in humans when scaled to the larger human ear. For
Conclusions and future directions
In the past decade, our capability to perform quantitative pharmacokinetic studies of the inner ear has improved dramatically. We now have fluid delivery and sampling techniques that have overcome serious technical artifacts that have plagued the field since its outset. We also have computer simulations of delivery and sampling procedures available for the ear that closely reproduce the measured data, allowing pharmacokinetic studies to be interpreted in detail in terms of amount and
Acknowledgement
Part of this work (ANS) was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) of the National Institutes of Health (NIH) under award number R01 DC001368. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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