Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications

Abstract

Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration.

Nanoparticle-based drug delivery in the inner ear: current challenges, limitations and opportunities

“…NP-based drug delivery offers numerous advantages over IT injections. With IT injections, the concentration of drug that comes into contact with the RWM determines the concentration delivered to the inner ear cavity [31,32]. The concentration of drug that does not reach the RWM is cleared through the Eustachian tube (ET).…”

Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug delivery

“…The clinical administration of drugs to the inner ear can be performed systemically or locally (1). The local intratympanic injection of drugs has generally been used since 1990 and is recognized as the most effective and least harmful current method.…”

“…The distribution of the drug in the inner ear depends on which window it enters the inner ear through and whether it is administered systemically or locally. The perilymph circulation in the inner ear is slow, and the blood-labyrinth barrier prevents a drug in the blood from entering the inner ear; both mechanisms make the systemic route for inner ear drug delivery inefficient (1). Moreover, the drug will accumulate in cochlea at only a low concentration; therefore, many methods are currently being investigated to improve the permeability of the RWM for local drug delivery.…”

Role of Glucocorticoids in Hearing Preservation in Partial Deafness Treatment

“…Absorption depends on lipophilicity and solubility of drugs. According to the data and publications, only a few medical substances can effectively be used in otorhinolaryngological practice due to achieving sufficient concentration in the inner ear [9]. Two main groups of drugs are used in clinical practice: aminoglycoside (mainly gentamicin) in pharmacotherapy of Meniere's disease [10] and corticosteroids (dexamethasone, triamcinolone and dexamethasone) in pharmacotherapy of idiopathic sudden sensorineural hearing loss (ISSHL) and other cases of acute hearing loss [11].…”