Tricyclic Antidepressants in Red Cells and Plasma: Correlation with Impaired Intraventricular Conduction in Acute Overdose

Amitai, Yona; Erickson, Timothy; Kennedy, Eugenia J.; Leikin, Jerrold B.; Hryhorczuk, Daniel O.; Noble, Jerrold; Hanashiro, Paul K.; Frischer, Henri

doi:10.1038/clpt.1993.133

Cited by 24 publications

(5 citation statements)

References 2 publications

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“…Free inhibitor concentrations were corrected for blood partitioning using the human values for ketoconazole (B:P ϭ 0.69) (Shibata et al, 2008), fluoxetine (B:P ϭ 0.55), and fluvoxamine (B:P ϭ 0.55) (McGinnity et al, 2008). A value of B:P was not found for clomipramine therefore a value of 1 was used because the analogs amitriptyline and imipramine have ratios less than 1, but their inhibitory desalkyl metabolites have compensating ratios greater than 1 (Amitai et al, 1993). An intermediate value of 35 ml/min/kg for dog liver blood flow was used.…”

Section: Methodsmentioning

confidence: 99%

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Mills

Zaya²,

Walters³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Recombinant cytochrome P450 (P450) phenotyping, different approaches for estimating fraction metabolized (f m ), and multiple measures of in vivo inhibitor exposure were tested for their ability to predict drug interaction magnitude in dogs. In previous reports, midazolam-ketoconazole interaction studies in dogs have been attributed to inhibition of CYP3A pathways. However, in vitro phenotyping studies demonstrated higher apparent intrinsic clearances (CL int,app ) of midazolam with canine CYP2B11 and CYP2C21. Application of activity correction factors and isoform hepatic abundance to liver microsome CL int,app values further implicated CYP2B11 (f m > 0.89) as the dog enzyme responsible for midazolam-and temazepam-ketoconazole interactions in vivo. Mean area under the curve (AUC) in the presence of the inhibitor/AUC ratios from intravenous and oral midazolam interaction studies were predicted well with unbound K i and estimates of unbound hepatic inlet inhibitor concentrations and intestinal metabolism using the AUC-competitive inhibitor relationship. No interactions were observed in vivo with bufuralol, although significant interactions with bufuralol were predicted with fluoxetine via CYP2D and CYP2C pathways (>2.45-fold) but not with clomipramine (<2-fold). The minor caffeine-fluvoxamine interaction (1.78-fold) was slightly higher than predicted values based on determination of a moderate f m value for CYP1A1, although CYP1A2 may also be involved in caffeine metabolism. The findings suggest promise for in vitro approaches to drug interaction assessment in dogs, but they also highlight the need to identify improved substrate and inhibitor probes for canine P450s.Metabolism-mediated drug interactions are an important consideration during preclinical drug lead optimization. Inhibitors of drugmetabolizing enzymes such as cytochromes P450 (P450) may be capable of decreasing the clearance of coadministered drugs when their clearance is metabolic. Therefore, it is important to evaluate new chemical entities as substrates and inhibitors of P450. To speed up this evaluation process, in vitro-in vivo extrapolation methods aimed at predicting metabolic drug interactions have continued to evolve. For instance, the choice of inhibition values (e.g., K i versus unbound K i ) (Brown et al., 2006), inhibitor absorption rates (Kanamitsu et al., 2000;Brown et al., 2005), P450 induction , and the choice of in vivo concentrations of P450 inhibitors (Brown et al., 2005;Obach et al., 2005) have all been studied with respect to in vitro-based drug-drug interaction (DDI) predictions. Irreversible enzyme inhibition mechanisms, although recognized for some time, have increasingly been added to in vitro-based drug interaction extrapolation methods with assumptions about the turnover rates of P450 isoforms (Mayhew et al., 2000;Venkatakrishnan and Obach, 2007). Several of these in vitro findings or approaches have even been integrated into several commercial software packages as biology continues to advance toward more physiolog...

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Section: Methodsmentioning

confidence: 99%

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Mills

Zaya²,

Walters³

et al. 2009

Drug Metab Dispos

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“…Neuroleptic drugs such as haloperidol and thioridazine have shown better correlation of RBC concentrations with therapeutic effects than plasma concentration . The RBC concentration of the metabolites of tricyclic antidepressants are believed to be the best toxicity markers for impaired intraventricular conduction . RBC has been one important tissue compartment for metformin in in vivo pharmacokinetics in human.…”

Section: Exposure: Effect Relationship Based On Tissue Concentrations...mentioning

confidence: 99%

“…115 The RBC concentration of the metabolites of tricyclic antidepressants are believed to be the best toxicity markers for impaired intraventricular conduction. 116 RBC has been one important tissue compartment for metformin in in vivo pharmacokinetics in human. The partitioning kinetics of metformin from RBCs to plasma is a slow process with a halflife of 32−39 h. Blood partitioning and efficient renal clearance of plasma metformin are considered the underlying causes, for metformin clinical half-life in plasma is 3−4× shorter than blood and RBCs.…”

Section: ■ Analytical Techniques and Tissues Used For Total Or Free T...mentioning

confidence: 99%

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation

et al. 2022

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The "free drug hypothesis" assumes that, in the absence of transporters, the steady state free plasma concentrations equal to that at the site of action that elicit pharmacologic effects. While it is important to utilize the free drug hypothesis, exceptions exist that the free plasma exposures, either at C max , C trough , and C average , or at other time points, cannot represent the corresponding free tissue concentrations. This "drug concentration asymmetry" in both total and free form can influence drug disposition and pharmacological effects. In this review, we first discuss options to assess total and free drug concentrations in tissues. Then various drug design strategies to achieve concentration asymmetry are presented. Last, the utilities of tissue concentrations in understanding exposure-effect relationships and translational projections to humans are discussed for several therapeutic areas and modalities. A thorough understanding in plasma and tissue exposures correlation with pharmacologic effects can provide insightful guidance to aid drug discovery.

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“…Für diesen Anstieg der Doxepin-Konzentration Än-derungen in Leberfunktion bzw. im Säure-Basen-Haushalt [27], Umverteilung innerhalb der Blutkompartimente [1], medikamentöse Interaktionen und die Hämoper-fusion zu diskutieren. Tierexperimentell konnte nachgewiesen werden, dass es tatsächlich zu einer Abnahme des Blutspiegels nach Antikörpertherapie infolge von Umverteilungsphänomenen kommt [24].…”

Section: Tab 2 Häufigkeit Verschiedener Symptome Im Rahmen Einer Akuunclassified

Intoxikation mit einem trizyklischen Antidepressivum

et al. 2007

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A 48-year-old woman with a major depression and treatment with doxepin was found comatose in her flat. Her son last saw her 48 h prior to being found. On arrival of the emergency physician, she presented a generalized seizure. The patient underwent endotracheal intubation and mechanical ventilation due to respiratory insufficiency and severe cyanosis. Empty packages of tablets (doxepin ca. 4000 mg and zolpidem 100 mg) were found in the flat. On hospital admission the doxepin blood concentration was 1.2 microg/ml. No life-threatening arrhythmia occurred at any time. On the advice of the poison information center, hemoperfusion was performed for extracorporeal elimination. Within several hours the doxepin blood concentration could be lowered to 0.8 microg/ml and although still above the therapeutic range the patient was extubated. However, the patient developed a generalized seizure which required re-intubation. As a consequence of the high distribution volume and re-distribution phenomena, the doxepin blood concentration had increased again to 1.2 microg/ml. Approximately 72 h later she was extubated again while the doxepin blood concentration was 0.9 microg/ml and 3 days later, the doxepin blood concentration was lowered to 0.3 microg/ml and the patient was transferred to the psychiatric ward the following day. This case report questions the efficacy of hemoperfusion during acute doxepin intoxication in the given constellation of a non-life-threatening arrhythmia.

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Tricyclic Antidepressants in Red Cells and Plasma: Correlation with Impaired Intraventricular Conduction in Acute Overdose

Cited by 24 publications

References 2 publications

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation

Intoxikation mit einem trizyklischen Antidepressivum

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