Pharmacokinetic-Pharmacodynamic Correlations of Antihistamines
Hartmut Derendorf, Günther Hochhaus in Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
In two separate studies, the pharmacokinetics and pharmacodynamics of terfenadine were investigated in 13 children with allergic rhinitis78 and in 8 healthy elderly female patients.58 In children and the elderly, the mean peak serum concentration of terfenadine metabolite I preceded the peak suppressive effect on wheal and flare by 2 to 3 h. The serum elimination half-life of metabolite I in children averaged 2.0 h and was shorter than the mean elimination half-life of 2.9 to 4.5 h in healthy young adults.77,79 On the other hand, the serum elimination half-life of metabolite I in the elderly was prolonged and averaged 8.7 h. In children, the wheal and flare areas were significantly inhibited from 2 to 8 h after intake and in the elderly the histamine-induced skin reactions were significantly suppressed from 2 to 24 h postdosing.
African Traditional Medicine
Charles Wambebe in African Indigenous Medical Knowledge and Human Health, 2018
Several biochemical and pharmacological mechanisms are involved in the metabolism of herbal medicines, which elicit body responses. In the metabolism of drugs, the initial elimination route, known as presystemic “first-pass” metabolism, involves the small intestine, the portal vein, and the liver. First-pass metabolic degradation often determines the peak and mean concentrations of an ingested drug, food supplement, or herbal medicine. Drugs such as terfenadine (an antihistamine formerly used for the treatment of allergic conditions), requires 100% presystemic, first-pass metabolism to convert it to its active and less toxic metabolite, terfenadine carboxylate. Like many other drugs and herbs, the metabolism and bioactivation of terfenadine involve oxidation by the cytochrome P450 microsomal enzyme system (Strandell et al., 2004; Chaudhary and Willett, 2006; Guengerich, 2008; Drugs.com, 2012). It has been shown that some natural bioactive compounds from plants and certain drugs could inhibit the enteric cytochrome P450 3A4 isozyme and produce toxic effects. For example, drugs such as erythromycin and ketoconazole, or foods such as grapefruit juice that inhibit or compete with these enzymes, will partially or completely block the metabolism of terfenadine and result in the absorption of unmetabolized terfenadine, with the potential for very serious toxic reactions including cardiac arrest and death (Bailey and Dresser, 2004; Drugs.com, 2012).
Information on level of drugs into breastmilk
Wendy Jones in Breastfeeding and Medication, 2013
Fexofenadine is a non-sedating anti-histamine. No adverse reports have been made on its use in lactation. Milk levels of fexofenadine have not been measured but data has been collected on the parent compound terfenadine (Lucas et al. 1995). In a telephone follow-up study of 25 infants exposed to terfendine, three mothers reported irritability in their infants but no medical attention was sought (Ito et al. 1993). Terfenadine itself was withdrawn from use following association with ventricular arrhythmias including torsade de pointes in some patients at high doses or in patients with liver disease. This effect has not been noted with the metabolite. It is licensed for use in children over 6 years. The BNF states that significant amounts of some anti-histamines are present in breastmilk. Although not known to be harmful manufacturers advise avoiding use in mothers who are breastfeeding. Probably compatible with breastfeeding but no data on levels fexofenadine transferring into breastmilk although there are studies on terfenadine. Observe infant for irritability. Use loratadine unless choice is essential. 158
The exploration of effect of terfenadine on Ca2+ signaling in renal tubular cells
Published in Journal of Receptors and Signal Transduction, 2019
He-Hsiung Cheng, Wei-Zhe Liang, Chun-Chi Kuo, Lyh-Jyh Hao, Chiang-Ting Chou, Chung-Ren Jan
Terfenadine acts as an antihistamine for treatment of allergic conditions [1]. Although terfenadine has been used by over 100 million patients worldwide as of 1990 [2], it was superseded by fexofenadine in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart [3]. In vitro, terfenadine also altered Ca2+ signaling in different models. It has been shown that terfenadine inhibited cytosolic Ca2+ dynamics in cultured guinea pig cardiomyocytes [4], and reduced Ca2+ influx, cyclic guanosine monophosphate (cGMP) formation, and N-methyl-D-aspartate (NMDA) receptor-dependent neurotoxicity following activation of L-type voltage sensitive Ca2+ channels in neurons [5]. Furthermore, terfenadine prevented L-type Ca2+ channel current in rat ventricular myocytes [6] and blocked time-dependent Ca2+, Na+, and K+ channels in guinea pig ventricular myocytes [7]. On the contrary, terfenadine-induced apoptosis in A375 human melanoma cells was mediated through elevation in cytosolic free Ca2+ levels ([Ca2+]i) [8]. Furthermore, terfenadine was reported to increase Ca2+ release in human atrial myocytes [9] and rat mast cells [10]. However, the effects of terfenadine on Ca2+ homeostasis in renal tubular cells have not been explored.
Association of H1-antihistamines with torsade de pointes: a pharmacovigilance study of the food and drug administration adverse event reporting system
Published in Expert Opinion on Drug Safety, 2021
Zahid Ali, Mohammad Ismail, Fahadullah Khan, Hira Sajid
Nonetheless, it is important to report several levels of evidence suggest that both new and previously known old signals (first- and second-generation H1A) pose a significant risk for causing TdP except fexofenadine based on our study findings. Although a case report has found a relationship between fexofenadine and QTIP and ventricular arrhythmia [35]. However, the close relationship of fexofenadine with cardiotoxic terfenadine (fexofenadine is a metabolite of terfenadine), patients with underlying QT-prolonging risk factors may need to be monitored with periodic ECG to watch for QT-prolongation and subsequent TdP. Moreover, worldwide several H1A are available as over-the-counter drugs without the need for a prescription for self-medication. Therefore, clinicians should prescribe these agents with great care while prescribing to patients at increased risk of QTIP and TdP until harmlessness has been proven. Additionally, in the future large clinical studies are highly warranted in order to thoroughly assess the potential association of H1A with TdP particularly new signals because H1A will continue to be a cornerstone of pharmacologic treatment in patients with allergic conjunctivitis, allergic rhinitis, and urticaria until the discovery of new safer agents for allergic conditions.
Terfenadine t-butyl hydroxylation catalyzed by human and marmoset cytochrome P450 3A and 4F enzymes in livers and small intestines
Published in Xenobiotica, 2018
Shotaro Uehara, Yukako Yuki, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine have been reported with concomitant administration of erythromycin or ketoconazole (Honig et al., 1992,1993) caused by P450 3A4-derived enzyme inhibition (Jurima-Romet et al., 1994; Yun et al., 1993). It has been suggested that roles of human P450 2J2 in the terfenadine oxidation may be an unrecognized participant in first-pass metabolism of terfenadine (Lee et al., 2010) but its contribution may be minor relative to that of P450 3A4. Marmoset and cynomolgus monkey P450 2J2 enzymes in small intestines and livers effectively metabolized human P450 2J2 probe substrates, astemizole and terfenadine (Uehara et al., 2016b). Marmoset P450 4F12 in small intestines and livers efficiently metabolized another anti-histaminic drug ebastine (Uehara et al., 2016c). Understanding the characteristics of marmoset or cynomolgus monkey P450 enzymes in extensive intestinal and hepatic clearances of terfenadine and its related P450 substrates would be important for non-human primates as preclinical drug metabolism research models.
Related Knowledge Centers
- Arrhythmia
- Fexofenadine
- Histamine
- Qt Interval
- Receptor Antagonist
- Metabolism
- Allergy
- Prodrug
- Antihistamine
- Peripherally Selective Drug