Pharmacokinetics of Diphenhydramine and a Demethylated Metabolite Following Intravenous And Oral Administration

Blyden, Gershwin T.; Greenblatt, David J.; Scavone, Joseph M.; Shader, Richard I.

doi:10.1002/j.1552-4604.1986.tb02946.x

Cited by 88 publications

(43 citation statements)

References 11 publications

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“…The reported steady-state plasma concentrations of amitriptyline, imipramine, and diphenhydramine in patients receiving therapeutic doses were approximately 0.2, 0.6, and 0.2 mM, respectively (Bailey and Jatlow, 1976a,b;Blyden et al, 1986). Based on these plasma concentrations and the determined K m values, it appears that UGT2B10 is the major enzyme responsible for their glucuronidation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Human UDP-Glucuronosyltransferase (UGT) 2B10 in DrugN-Glucuronidation: Substrate Screening and Comparison with UGT1A3 and UGT1A4

et al. 2013

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Recent observations revealed that human UDP-glucuronosyltransferase (UGT) 2B10 catalyzes N-glucuronidation of amine-containing compounds. Knowledge of the substrate specificity and clinical significance of UGT2B10 is still limited. The purpose of this study was to expand the knowledge of UGT2B10 substrates and to evaluate its significance in drug clearance. Using recombinant UGT2B10, we found that it catalyzes the N-glucuronidation of amitriptyline, imipramine, ketotifen, pizotifen, olanzapine, diphenhydramine, tamoxifen, ketoconazole, and midazolam. These are drugs that were previously reported to be substrates for UGT1A4 or UGT1A3, and that contain in their structure either tertiary aliphatic amines, cyclic amines, or an imidazole group. UGT2B10 was inactive in the glucuronidation of desipramine, nortriptyline, carbamazepine, and afloqualone. This group of drugs contains secondary or primary amines, and these results suggest that UGT2B10 preferably conjugates tertiary amines. This preference is partial because UGT2B10 did not conjugate the tertiary cyclic amine in trifluoperazine. Kinetic analyses revealed that the affinity and clearance of UGT2B10 for amitriptyline, imipramine, and diphenhydramine are significantly higher than the corresponding values of UGT1A4 and UGT1A3, although the V max values of UGT1A4 toward these drugs are considerably higher. These findings suggest that UGT2B10 plays a major role in the N-glucuronidation of these drugs at therapeutic concentrations. These results are also supported by inhibition studies with nicotine and hecogenin. In conclusion, this study expands the understanding of the substrate specificity of UGT2B10, highlighting its preference for tertiary amines with higher affinities and clearance values than those of UGT1A4 and UGT1A3.

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Section: Discussionmentioning

confidence: 99%

Human UDP-Glucuronosyltransferase (UGT) 2B10 in DrugN-Glucuronidation: Substrate Screening and Comparison with UGT1A3 and UGT1A4

et al. 2013

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“…1 4 This was attributed to the short duration of effect of the drug. 10,14 Thus, we decided to give a second dose of both drugs six hours after the first administration since the plasma half life of both drugs, metoclopramide and dimenhydrinate, is similar (about 4-6 hr 15,16 ).…”

Section: Discussionmentioning

confidence: 99%

Dimenhydrinate and metoclopramide alone or in combination for prophylaxis of PONV

Eberhart

Seeling

Ulrich

et al. 2000

Can J Anesth/J Can Anesth

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Purpose: Dimenhydrinate and metoclopramide are inexpensive antiemetic drugs. Metoclopramide, especially, has been studied extensively in the past, but there are no studies on the combination of both drugs for prevention of postoperative nausea and vomiting (PONV).Methods: One hundred and sixty male inpatients undergoing endonasal surgery were randomized to receive one of four antiemetic regimens in a double-blind manner: placebo, 1 mg·kg -1 dimenhydrinate, 0.3 mg·kg -1 metoclopramide, or the combination of both drugs was administered after induction of anesthesia. Patients received a second dose of these drugs six hours after the first administration to mitigate their short half-life. Standardized general anesthesia included benzodiazepine premedication, propofol, desflurane in N 2 O/O 2 vecuronium, and a continuous infusion of remifentanil. Postoperative analgesia and antiemetic rescue medication were standardized. Episodes of vomiting, retching, nausea, and the need for additional antiemetics were recorded for 24 hr. The incidences of PONV were analyzed with Fisher´s Exact test and the severity of PONV (rated by a standardized scoring algorithm) with the Jonckheere-Terpestra-test. Results:The incidence of patients free from PONV was 62.5% in the placebo-group and increased to 72.5% in the metoclopramide-group (P = 0.54), 75.0% in the dimenhydrinate-group (P = 0.34), and 85.0% in the combination-group (P = 0.025). In the latter group, the severity of PONV was reduced compared with placebo treatment (P = 0.017; Jonckheere-Terpestra-test).Conclusion: Dimenhydrinate and metoclopramide were ineffective in reducing the incidence and the severity of PONV. Their combination reduced the incidence of PONV compared with placebo.Objectif : Le dimenhydrinate et le métoclopramide sont des antiémétiques pas chers. Beaucoup d'études ont déjà été faites, avec le métoclopramide surtout, mais aucune avec la combinaison des deux comme moyen de prévention des nausées et des vomissements postopératoires (NVPO).Méthode : Cent soixante patients masculins qui devaient subir une intervention endonasale ont consenti à participer à une étude prospective, randomisée et en double aveugle, et à recevoir un des quatre traitements antiémétiques suivants : un placebo; 1 mg·kg-1 de dimenhydrinate; 0,3 mg·kg-1 de métoclopramide ou une combinaison des deux médicaments après l'induction de l'anesthésie. Ceux qui ont reçu du dimenhydrinate ou les deux médicaments ont eu une seconde dose de dimenhydrinate six heures après la première étant donné la courte demi-vie de ce médicament. L'anesthésie générale standardisée comprenait une prémédication de benzodiazépine, du propofol, du desflurane dans un mélange de N 2 O/O 2 , du vécuronium et une perfusion continue de rémifentanil. L'analgésie postopératoire et les antiémétiques de rattrapage ont été standardisés. Les nausées, les vomissements, les efforts pour vomir et les demandes d'antiémétiques additionnels ont été enregistrés pendant 24 h. Les incidences de NVPO ont été analysées selon le test Exact ...

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“…There were, however, nine level 1b studies (individual randomized clinical trials) that were reviewed in which therapeutic doses (ranging from 37.5 to 75 mg) of diphenhydramine were administered to generally healthy volunteers of varying ages (37)(38)(39)(40)(41)(42)(43)(44)(45). No serious toxicity was noted in these studies.…”

Section: Diphenhydramine: Acute Exposures In Patients 6 Years Of Age mentioning

confidence: 99%

Diphenhydramine and Dimenhydrinate Poisoning: an Evidence-Based Consensus Guideline for Out-of-Hospital Management

Scharman

Erdman

Wax

et al. 2006

Clinical Toxicology

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Pharmacokinetics of Diphenhydramine and a Demethylated Metabolite Following Intravenous And Oral Administration

Cited by 88 publications

References 11 publications

Human UDP-Glucuronosyltransferase (UGT) 2B10 in DrugN-Glucuronidation: Substrate Screening and Comparison with UGT1A3 and UGT1A4

Human UDP-Glucuronosyltransferase (UGT) 2B10 in DrugN-Glucuronidation: Substrate Screening and Comparison with UGT1A3 and UGT1A4

Dimenhydrinate and metoclopramide alone or in combination for prophylaxis of PONV

Diphenhydramine and Dimenhydrinate Poisoning: an Evidence-Based Consensus Guideline for Out-of-Hospital Management

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