Terfenadin

The sales of antagonists of receptors, eg, diphenhydramine, terfenadine, and astemizole, used in the treatment of allergic diseases, represent 1% of the overall pharmaceutical market, ie, 1.7 biUion (U.S.). antagonists, eg, cimetidine and ranitidine, are effective in peptic ulcer disease and esophageal reflux. Sales represent 3.5% of the world market, ie, 6 biUion (U.S.). agonists or antagonists have not yet found a clear indication. 

Two newer potent selective H -antagonists, terfenadine (23) (132) and astemizole (24) (133), have been developed which have neither the sedative nor the anticholinergic Habilities of the earlier agents. Both of these compounds have proven efficacious in the treatment of hay fever and produce very few side effects, prompting a re-evaluation of the role of antihistamines in asthma treatment. 

Oral terfenadine has a relatively rapid onset (134), and a sufficiently long duration of action that it needs to be dosed only once or twice a day. 

The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agoits, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),... 

The search for nonsedating H-1 antihistamines met its first success in terfenadine (see 198, Chapter 2). A different approach aimed at keeping such agents out of the CNS, by prevent-... 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

Fig. 7-14. Separation of terfenadine and MDL 16,455 methyl ester on Chiralpak AD , (a) Terfenadine Chiralpak AD 250-4.6, w-hexane/2-propanol (90 10), flowrate 1.0 ml min, UV-detection 224 nm. (b) MDL 16,455 methyl ester Chiralpak AD 250-4.6, w-hexane/2-propanol (90 10), flowrate 1.0 ml min , UV-detec-tion 224 nm. (Reproduced with permission from A. Terhechte, PhD Thesis, University of Munster, Munster, 1993 [24].)...

Asternizole, terfenadine Ketoconazole, erythromycin, etc. CYP3A4 Ventricular, arrhythmia... 

Ruelle, J. A., Tsinman, 0., Avdeef, A. Acid-base cosolvent method for determining aqueous permeability of amiodarone, itraconazole, tamoxifen, terfenadine and other very insoluble molecules. Chem. Pharm. Bull. 2004, 52, 551-555. 

In some patients, torsades de pointes maybe of short duration and may terminate spontaneously. However, torsades de pointes may not terminate on its own, and if left untreated, may degenerate into VF and result in sudden cardiac death.13 Several drugs, including terfenadine, astemizole, and cisapride have been withdrawn from the United States market as a result of causing deaths due to torsades de pointes. 

CYP3A4 is highly inducible by a large variety of commonly prescribed and utilized synthetic drugs (e.g., carbamazepine) and plant products (e.g., St. John s wort) (Roby, Anderson et al, 2000), and at the same time also is potently inhibited by various other medications (e.g., terfenadine and ketoconazole) (Jurima-Romet, Crawford etal, 1994) as well as common foodstuffs (e.g., grapefruit juice) (Oesterheld 8c Kallepalli, 1997). Since individual and ethnic/cultural groups vary dramatically in their exposure to these inducers and inhibitors, it stands to reason that... 

Jurima-Romet, M., Crawford, K. et al. (1994). Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab. Dispos., 22(6), 849-57. 

Antihistamine astemizole, terfenadine Estrogen ethinyl estradiol GI cisapride... 

Figure 6.12 Correction of the apparent solubility pH profile (solid curves) for the effect of DMSO and/or aggregation (a) chlorpromazine (b) terfenadine (c) piroxicam (d) phen-azopyridine. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

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