Effect of Lipophilicity on in Vivo Iontophoretic Delivery. II. .BETA.-Blockers.

Abstract

Transdermal drug absorption includes several sequential processes, as follows: (1) drug absorption into the skin; (2) transfer from skin to cutaneous vein; (3) transport to systemic circulation by blood flow. In systemic therapy, it is necessary to transfer drug molecules from skin (application site) to cutaneous blood flow and to transport to the target organ through systemic circulation. [2][3][4][5][6][7] On the other hand, local therapy needs to accumulate drug molecules at the local site (skin, muscle and joint, etc.), but not to eliminate into the blood flow.2-7) Therefore, the evaluation of drug transfer properties into local blood flow would be expected to predict the systemic and local therapeutic effects.Previously, we have developed a method to investigate transdermal absorption processes in vivo, whereby the drug concentrations in skin, cutaneous vein and systemic vein are measured after iontophoretic delivery of drugs to rats. 8) Further, kinetic analysis of drug transfer from skin to cutaneous vein has been established by modifying a physiological pharmacokinetic model. 9) In the previous study, we investigated the effect of drug lipophilicity on the iontophoretic transdermal absorption of non-steroidal anti-inflammatory drugs (NSAIDs) such as salicylic acid, ketoprofen, naproxen and indomethacin.10) The transfer properties of these NSAIDs from skin to cutaneous vein decreased with an increase in their lipophilicity.The NSAIDs examined previously are acidic drugs with a carboxyl group. In the present study, b-blockers were selected as basic drugs having an amino group and included atenolol (AT), pindolol (PD), metoprolol (MP), acebutolol (AB), oxprenolol (OX) and propranolol (PP). The chemical structures and physicochemical properties are listed in Table 1. 11-13) These b-blockers are adequate for evaluating the effect of lipophilicity on transdermal absorption properties, because the molecular weights are of narrow range. As an indication of drug lipophilicity, we used the logarithm of n-octanol/buffer partition coefficient (Log P), which varied from Ϫ0.11 to 1.49 (pH 7.4, 37°C).12) The difference in the lipophilicity is a consequence of the difference in the aromatic substituents of the b-blockers.Beta-blockers are used in the treatment of hypertension, angina pectoris and cardiac arrhythmia.14) Because of their short elimination half-life (from several to less than 6 h), 15) sustained release formulations for oral administration have been developed to prolong the therapeutic effects.16-21) However, the oral absorption of b-blockers is influenced by hepatic first-pass metabolism. 15,22) Thus, the development of transdermal delivery systems may be expected to achieve good maintenance of optimal blood levels and the avoidance of first-pass effects. Anodal Iontophoresis Anodal iontophoresis was performed as described previously. 10) Briefly, male SpragueDawley rats (8-10 weeks old, Charles River Japan) were anesthetized with ether throughout the experiment, and their body temperature was maintained...

Liposomal Encapsulation for Systemic Delivery of Propranolol via Transdermal Iontophoresis Improves Bone Microarchitecture in Ovariectomized Rats

“…The current density of 0.1 mA was applied to stimulate the permeation of PRP or PRP encapsulated liposomes. The location of anode and cathode was placed according to the investigation on β-blocker iontophoresis accomplished by Tashiro et al [44]. The duration of each experiment was conducted for 2 h per day, 2 days per week, for 12 weeks.…”

Quantitative structure–permeation relationship for iontophoretic transport across the skin

“…Instead, the literature contains transport numbers which have been determined under a wide variety of experimental conditions, using electrodes and formulations comprising diverse background electrolytes and buffers. This is the case even in certain investigations which have attempted to identify the influence of molecular properties (such as molecular weight, logP, specific conductivity) on iontophoretic transport [5][6][7][8][9][10][24][25][26]. That such studies have not been able to fully reveal fundamental patterns of behaviour can be explained by the significant presence of competing co-and counter-ions, which greatly affect the transport number of the drug of interest; the latter, under these circumstances, is no longer an intrinsic property of the ion itself.…”

Comparison of Dialysis and Dispersion Methods for In Vitro Release Determination of Drugs from Multilamellar Liposomes

“…Yet, in studies on transdermal permeation, the skin flux reported for pindolol was much higher than expected based on its lipophilicity, which was attributed to the unique nature of the indole group (heterocyclic ring) as an aromatic substituent (7).…”