Drugs online research references
Drug Metab Dispos. 1998 Jun;26(6):536-9.
In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists.
Hamelin BA, Bouayad A, Drolet B, Gravel A, Turgeon J.
Quebec Heart Institute, Laval Hospital, Quebec, Canada G1V 4G5.
Classic antihistamines, namely diphenhydramine, chlorpheniramine, clemastine, perphenazine, hydroxyzine, and tripelennamine, share structural features with substrates and inhibitors of the polymorphic cytochrome P450 (CYP) isozyme CYP2D6. Therefore, the current study was undertaken to characterize the in vitro inhibition of CYP2D6 by these commonly used, histamine H1 receptor antagonists. Microsomal incubations were performed using bufuralol as a specific CYP2D6 substrate and microsomes derived from human cells transfected with CYP2D6 cDNA. Reaction velocities were assessed in the absence and presence of antihistamines (20 microM) at 11 substrate concentrations (1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, and 100 microM), as well as at three nonsaturating substrate concentrations (2.5, 5, and 20 microM) and three inhibitor concentrations (5, 20, and 50 microM). In the presence of all antihistamines, the Vmax and KM of bufuralol 1'-hydroxylation were significantly altered, compared with the uninhibited reaction (p < 0.05). Lineweaver-Burke plots suggested competitive inhibition of the reaction by diphenhydramine and mixed inhibition by all other antihistamines tested. Diphenhydramine and chlorpheniramine, with estimated Ki values of approximately 11 microM, were the weakest inhibitors of CYP2D6 in vitro. Whereas tripelennamine, promethazine, and hydroxyzine were similar in their inhibitory capacities (Ki approximately 4-6 microM), clemastine appeared to be significantly more potent, with a Ki of approximately 2 microM. These data demonstrate that classic histamine H1 receptor antagonists, available in over-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the range of their expected hepatic blood concentrations, suggesting that, under specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9616188&dopt=Abstract
J Cardiovasc Pharmacol. 1998 Jul;32(1):123-8.
"Conventional" antihistamines slow cardiac repolarization in isolated perfused (Langendorff) feline hearts.
Wang WX, Ebert SN, Liu XK, Chen YW, Drici MD, Woosley RL.
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA.
We examined the effects of "conventional" antihistamines on cardiac repolarization by using the isolated perfused feline heart model. Representative drugs from the major classes of antihistamines were tested. Each of the antihistamines evaluated in this study elicited a dose-dependent slowing of cardiac repolarization, as indicated by the QT prolongations observed from electrocardiogram (ECG) tracings recorded during these experiments. The concentrations of drugs tested ranged from 1 to 30 microM. Of the drugs analyzed, clemastine and hydroxyzine appeared to be the most potent (relative EC50 values, 5.2 and 6.6 microM, respectively), causing the QT to lengthen by as much as 40-50% at a concentration of 10 microM. Brompheniramine, chlorpheniramine, and diphenhydramine displayed intermediate potencies with respect to QT prolongation (relative EC50 values, 11-13 microM), whereas cyproheptadine, chlorcyclizine, and promethazine were the least potent of the antihistamines tested (relative EC50 values, 16-20 microM). It is concluded that the antihistamines evaluated in this study act directly on the heart to slow cardiac repolarization. These findings could have important clinical relevance for patients taking excessive dosages of conventional antihistamines and those at risk of developing cardiac arrhythmias.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9676731&dopt=Abstract
Pharmacology. 1998 Aug;57(2):57-64.
Antitussive action of antihistamines is independent of sedative and ventilation activity in the guinea pig.
McLeod RL, Mingo G, O'Reilly S, Ruck LA, Bolser DC, Hey JA.
Schering Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
We studied the oral actions of antihistamines from six chemical classes, namely: the ethanolamines (ENA, diphenhydramine and clemastine); ethylenediamines (EDA, pyrilamine and tripelennamine); piperidines (PPD, terfenadine and astemizole); piperazines (PPZ, hydroxyzine and cetirizine); phenothiazines (PTZ, promethazine), and the alkylamines (ALA, chlorpheniramine and bromopheniramine) on cough reflexes, pentobarbital-induced sedation and minute ventilation in the conscious guinea pig. Antihistamines of the ENA class had minimal effects on capsaicin-induced cough although both diphenhydramine (30 and 100 mg/kg p.o.) and clemastine (30 and 100 mg/kg p.o.) increased sedation time (ST). The PPZ class demonstrated both antitussive and sedating activity. The minimum effective oral antitussive dose (MED) of cetirizine and hydroxyzine was 30 and 10 mg/kg, respectively. The EDA did not exhibit antitussive activity. Tripelennamine (10, 30 and 100 mg/kg p.o.) but not pyrilamine enhanced ST. The MED for the PTZ, promethazine, was 10 mg/kg, and at 100 mg/kg promethazine increased ST. The ALA group displayed antitussive activity but only chlorpheniramine (10 mg/kg p. o.) had any effects on ST. The MED for chlorpheniramine and bromopheniramine was 3 and 10 mg/kg p.o., respectively. The PPD antihistamines, namely terfenadine and astemizole, inhibited cough (MED 30 and 10 mg/kg p.o.) without sedative effects. Of the antihistamines tested only promethazine (100 mg/kg p.o.) depressed ventilation responses; however, this dose of promethazine was associated with adverse behavioral effects. The present findings indicate that the antitussive actions of antihistamines are not directly related to histamine H1-receptor blockade because several antihistamines did not antagonize capsaicin-induced cough. In addition, the antitussive actions of antihistamines are independent of their sedative or ventilation effects.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9691225&dopt=Abstract
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