High dissociation constants (pKa) of basic permeants are associated with in vivo skin irritation in man

Nangia, Avinash; Andersen, P. H.; Berner, Bret; Maibach, Howard I.

doi:10.1111/j.1600-0536.1996.tb02192.x

Cited by 45 publications

(14 citation statements)

References 17 publications

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“…Furthermore, drugs that possess pKa values greater than 8 have been shown to irritate the skin as well. A trend of increasing irritation with increasing pKa was reported by a number of groups [82,83]. Based on these studies, it is predicted that drugs with pKa values between 4 and 8 should provide minimal skin irritation.…”

Section: Challenges and Solutions For Overcoming Skin Irritationmentioning

confidence: 88%

Challenges and Opportunities in dermal/transdermal Delivery

Paudel

Milewski

Swadley

et al. 2010

Therapeutic Delivery

498

264

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Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs. Further advances in transdermal delivery depend on the ability to overcome the challenges faced regarding the permeation and skin irritation of the drug molecules. Emergence of novel techniques for skin permeation enhancement and development of methods to lessen skin irritation would widen the transdermal market for hydrophilic compounds, macromolecules and conventional drugs for new therapeutic indications. As evident from the ongoing clinical trials of a wide variety of drugs for various clinical conditions, there is a great future for transdermal delivery of drugs.Delivery of drugs through the skin has been an attractive as well as a challenging area for research. Advances in modern technologies are resulting in a larger number of drugs being delivered transdermally including conventional hydrophobic small molecule drugs, hydrophilic drugs and macromolecules. Transdermal systems are a desirable form of drug delivery because of the obvious advantages over other routes of delivery. Transdermal delivery provides convenient and pain-free self-administration for patients. It eliminates frequent dosing administration and plasma level peaks and valleys associated with oral dosing and injections to maintain a constant drug concentration, and a drug with a short halflife can be delivered easily. All this leads to enhanced patient compliance, especially when long-term treatment is required, as in chronic pain treatment and smoking cessation therapy. Avoidance of hepatic first-pass metabolism and the GI tract for poorly bioavailable drugs is another advantage of transdermal delivery. Elimination of this first-pass effect allows the amount of drug administered to be lower, and hence safer in hepato-compromised patients, resulting in the reduction of adverse effects. Transdermal systems are generally inexpensive when compared with other therapies on a monthly cost basis, as patches are designed to deliver drugs from 1 to 7 days. The other advantage of transdermal delivery is that multiple dosing, on-demand or variable-rate delivery of drugs, is possible with the latest programmable systems, adding more benefits to the conventional patch dosage forms. The general acceptability of transdermal products by patients is very high, which is also evident from the increasing market for transdermal products. The transdermal drug delivery market, worth $12.7 billion dollars in 2005, is expected to reach $32 billion in 2015 [1].

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Section: Challenges and Solutions For Overcoming Skin Irritationmentioning

confidence: 88%

Challenges and Opportunities in dermal/transdermal Delivery

Paudel

Milewski

Swadley

et al. 2010

Therapeutic Delivery

498

264

View full text Add to dashboard Cite

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“…5 and Table 2). Since mecamylamine is a relatively strong base (p K a = 11.4; Nangia et al, 1996) it exists mainly in the protonated state at physiological pH and thus, the protonated mode of interaction (see Fig. 8C) should dominate in the hα4β2 ion channel.…”

Section: Discussionmentioning

confidence: 99%

Tricyclic antidepressants and mecamylamine bind to different sites in the human α4β2 nicotinic receptor ion channel

Arias

Rosenberg²,

Targowska-Duda

et al. 2010

The International Journal of Biochemistry & Cell Biology

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The interaction of tricyclic antidepressants with the human (h) α4β2 nicotinic acetylcholine receptor in different conformational states was compared with that for the noncompetitive antagonist mecamylamine by using functional and structural approaches. The results established that: (a) [3H]imipramine binds to hα4β2 receptors with relatively high affinity (Kd = 0.83 ± 0.08 μM), but imipramine does not differentiate between the desensitized and resting states, (b) although tricyclic antidepressants inhibit (±)-epibatidine-induced Ca2+ influx in HEK293-hα4β2 cells with potencies that are in the same concentration range as that for (±)-mecamylamine, tricyclic antidepressants inhibit [3H]imipramine binding to hα4β2 receptors with affinities >100-fold higher than that for (±)-mecamylamine. This can be explained by our docking results where imipramine interacts with the leucine (position 9′) and valine (position 13′) rings by van der Waals contacts, whereas mecamylamine interacts electrostatically with the outer ring (position 20′), (c) van der Waals interactions are in agreement with the thermodynamic results, indicating that imipramine interacts with the desensitized and resting receptors by a combination of enthalpic and entropic components. However, the entropic component is more important in the desensitized state, suggesting local conformational changes. In conclusion, our data indicate that tricyclic antidepressants and mecamylamine efficiently inhibit the ion channel by interacting at different luminal sites. The high proportion of protonated mecamylamine calculated at physiological pH suggests that this drug can be attracted to the channel mouth before binding deeper within the receptor ion channel finally blocking ion flux.

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“…56,57 As well as its influence on gastrointestinal absorption, ionization is important in the transport and disposition of drugs in other organs and biological fluids. 59 In forensic investigations of drugs of abuse, secretion into saliva is suggested to be by passive diffusion and to depend on lipid solubility, pK a , plasma protein binding, and the pH of saliva. 58 Irritation caused by 12 basic drugs with pK a values between 1.4 and 11.2 applied to the skin increased significantly with increasing pK a , the drugs which are ionized at skin pH causing the greatest irritation.…”

Section: Other Connections Between Pk a And Drugsmentioning

confidence: 99%