scholarly journals Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Johannes Matthaei ◽  
Jürgen Brockmöller ◽  
Werner Steimer ◽  
Konstanze Pischa ◽  
Stefan Leucht ◽  
...  
Keyword(s):  
Genetic Polymorphism ◽  
Depressive Disorder ◽  
Healthy Volunteers ◽  
Organic Cation ◽  
Plasma Concentrations ◽  
Organic Cation Transporter ◽  
Independent Study ◽  
Interindividual Variation ◽  
Cyp2d6 Genotype ◽  
The Impact

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.

scholarly journals Viscoelastometry for detecting oral anticoagulants

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Philipp Groene ◽  
Daniela Wagner ◽  
Tobias Kammerer ◽  
Lars Kellert ◽  
Andreas Giebl ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Prospective Observational Study ◽  
Oral Anticoagulants ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Clotting Time ◽  
Emergency Situations ◽  
Tissue Plasminogen ◽  
The Impact

Abstract Background Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. Methods This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17–525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). Results 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors. Conclusions In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking. Trial registration German clinical trials database ID: DRKS00015302.

scholarly journals Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers

2016 ◽  
Vol 19 (2) ◽  
pp. 198 ◽  
Author(s):  
Ioana Todor ◽  
Adina Popa ◽  
Maria Neag ◽  
Dana Muntean ◽  
Corina Bocsan ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Cyp2d6 Activity ◽  
The Mean ◽  
The Impact ◽  
Pharmacokinetic Drug

Purpose: To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers. Methods: An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods. Results: Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞  were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively. Conclusions: These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Cytochrome P450 2D6 status predicts breast cancer relapse in women receiving adjuvant tamoxifen (Tam)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 504-504 ◽  
Author(s):  
S. K. Knox ◽  
J. N. Ingle ◽  
V. J. Suman ◽  
J. M. Rae ◽  
D. A. Flockhart ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Plasma Concentrations ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
Rank Test ◽  
Cyp2d6 Genotype ◽  
Medication History ◽  
Concurrent Administration ◽  
The North ◽  
The Impact

504 Background: CYP2D6 genetic variants and concurrent administration of potent inhibitors (Inh) of the enzyme markedly reduce the plasma concentrations of endoxifen (Jin. JNCI 2005;97:30–9). We have shown that genetic variation in CYP2D6 is associated with a higher risk of relapse in Tam treated patients (pts) (Goetz. JCO 2005;23:9312–18), but the impact of CYP2D6 inhibition on Tam clinical outcome is unknown. Methods: Using the North Central Cancer Treatment Group 89–30–52 adjuvant Tam trial (1989–1994), we evaluated the effect of co-administration of CYP2D6 Inh and CYP2D6*4 genotype on relapse in pts receiving tam alone. Patient charts were reviewed at each randomizing site to record the following known CYP2D6 Inh: fluoxetine (F), paroxetine (P), sertraline (S), cimetidine (C), amiodarone (A), doxepin (D), ticlopidine (T) and haloperidol (H). Poor metabolizers (PM) were defined as pts who were CYP2D6 *4/*4 and/or known to receive a CYP2D6 Inh. Intermediate metabolizers (IM) were defined as WT/*4 without CYP2D6 Inh, and extensive metabolizers (EM) as WT/WT without CYP2D6 Inh. The association between CYP2D6 status and Tam clinical outcome was determined using the log-rank test. Multivariate Cox modeling was performed using traditional prognostic factors. Results: CYP2D6*4 genotype was obtained in 190 of 256 eligible pts, with a CYP2D6*4/*4 genotype frequency of 6.8% as described previously (Goetz JCO 2005). Medication history was available in 171/256 eligible pts and in 143/190 pts with CYP2D6 genotype. Eleven of 173 patients were concomitantly administered these CYP2D6 Inh: F(2), P(2), S(2), H(1), C(4), and D(1). The median duration of use was 2.5 yrs. Twenty-four pts met criteria for PM [13 by *4/*4 genotype and 11 by CYP2D6 Inh (7 WT/WT, 1 WT/*4, and 3 unknown genotype)], 21 for IM, and 102 for EM. Compared with either IM or EM, PMs had significantly worse time to recurrence and disease free survival in both the univariate (HR 2.5, p=0.02; and 2.2, p=0.01) and multivariate (HR 2.7, p=0.01; and HR 2.2 p=.02) analyses utilizing tumor size, nodal status, and tumor grade. Conclusion: Our data indicate that CYP2D6 status can be used to identify pts who should receive tam therapy and tam treated pts should not be co-administered potent CYP2D6 inhibitors. No significant financial relationships to disclose.

scholarly journals Assessing Exposure to Lignans and Their Metabolites in Humans

2006 ◽  
Vol 89 (4) ◽  
pp. 1174-1181 ◽  
Author(s):  
Johanna W Lampe ◽  
Charlotte Atkinson ◽  
Meredith A J Hullar
Keyword(s):  
Glucuronic Acid ◽  
Plasma Concentrations ◽  
Intestinal Bacteria ◽  
Intestinal Wall ◽  
Biologically Active ◽  
Interindividual Variation ◽  
Internal Factors ◽  
Sources Of Variation ◽  
The Impact ◽  
Dose Dependent

Abstract Phytoestrogens occur naturally in plants and are structurally similar to mammalian estrogens. The lignans are a class of phytoestrogen and can be metabolized to the biologically active enterolignans, enterodiol, and enterolactone by a consortium of intestinal bacteria. Secoisolariciresinol diglucoside (SDG), a plant lignan, is metabolized to enterodiol and, subsequently, enterolactone. Matairesinol, another plant lignan, is metabolized to enterolactone. Other dietary enterolignan precursors include lariciresinol, pinoresinol, syringaresinol, arctigenin, and sesamin. Enterolignan exposure is determined in part by intake of these precursors, gut bacterial activity, and host conjugating enzyme activity. A single SDG dose results in enterolignan appearance in plasma 810 h latera timeframe associated with colonic bacterial metabolism and absorption. Conjugation of enterolignans with sulfate and glucuronic acid occurs in the intestinal wall and liver, with the predominant conjugates wall and liver, with the predominant conjugates have demonstrated dose-dependent urinary lignan excretion in response to flaxseed consumption (a source of SDG); however, even in the context of controlled studies, there is substantial interindividual variation in plasma concentrations and urinary excretion of enterolignans. The complex interaction between colonic environment and external and internal factors that modulate it likely contribute to this variation. Knowledge of this field, to date, indicates that understanding the sources of variation and measuring the relevant panel of compounds are important in order to use these measures effectively in evaluating the impact of lignans on human health.

scholarly journals Plasma concentrations of granulocyte colony-stimulating factor (G-CSF) in patients with substance use disorders and comorbid major depressive disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sandra Torres Galván ◽  
María Flores-López ◽  
Pablo Romero-Sanchiz ◽  
Nerea Requena-Ocaña ◽  
Oscar Porras-Perales ◽  
...  
Keyword(s):  
Substance Use ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Plasma Concentrations ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Major Depressive ◽  
The Impact ◽  
Stimulating Factor ◽  
Factor G

AbstractGranulocyte colony–stimulating factor (G-CSF) has raised much interest because of its role in cocaine addiction in preclinical models. We explored the plasma concentrations of G-CSF in patients diagnosed with substance use disorder (SUD) and highly comorbid psychiatric disorders. In particular, we investigated the association between G-CSF concentrations and comorbid major depressive disorder (MDD) in patients with cocaine and alcohol use disorders (CUD and AUD, respectively). Additionally, patients with MDD but not SUD were included in the study. Three hundred and eleven participants were enrolled in this exploratory study: 136 control subjects, 125 patients with SUD (SUD group) from outpatient treatment programs for cocaine (N = 60, cocaine subgroup) and alcohol (N = 65, alcohol subgroup), and 50 patients with MDD but not SUD (MDD group) from primary-care settings. Participants were assessed based on DSM-IV-TR criteria, and a blood sample was collected to examine the plasma concentrations of G-CSF. G-CSF concentrations were negatively correlated with age in the entire sample (r = − 0.233, p < 0.001) but not in the patients with MDD. G-CSF concentrations were lower in patients with SUD than in controls (p < 0.05), specifically in the cocaine subgroup (p < 0.05). Patients with SUD and comorbid MDD had lower G-CSF concentrations than patients with SUD but not comorbid MDD or controls (p < 0.05). In contrast, patients with MDD but not SUD showed no differences compared with their controls. The negative association between G-CSF concentrations and age in the sample was not observed in patients with MDD. G-CSF concentrations were decreased in patients with SUD and comorbid MDD but not in patients with MDD. Therefore, G-CSF may be useful to improve the stratification of patients with dual diagnosis seeking treatment. Further investigation is needed to explore the impact of sex and type of drug on the expression of G-CSF.

Organic cation transporter 3 ist im hepatischen Kupfermetabolismus involviert

2018 ◽  
Vol 56 (08) ◽  
pp. e250-e250
Author(s):  
S Guttmann ◽  
S Reinartz Groba ◽  
C Niemietz ◽  
V Sandfort ◽  
A Zibert ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Organic Cation Transporter 3

Pharmacokinetics and Effects on Fibrinolytic and Coagulation Parameters of Two Doses of Recombinant Tissue-Type Plasminogen Activator in Healthy Volunteers

1986 ◽  
Vol 56 (01) ◽  
pp. 001-005 ◽  
Author(s):  
M Verstraete ◽  
C A P F Su ◽  
P Tanswell ◽  
W Feuerer ◽  
D Collen
Keyword(s):  
Healthy Volunteers ◽  
Plasminogen Activator ◽  
Degradation Products ◽  
Plasma Concentrations ◽  
State Level ◽  
Compartment Model ◽  
Tissue Type ◽  
Maximum Plasma ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryPharmacokinetics and pharmacological effects of two intravenous doses of recombinant tissue-type plasminogen activator (rt-PA) (40 and 60 mg over 90 min) were determined in healthy volunteers. Mean maximum plasma concentrations were 1080 and 1560 ng/ml respectively. The steady state level during subsequent maintenance infusion of 30 mg over 6 h was 250 ng/ml. The pharmacokinetics of rt-PA showed a bi-exponential disappearance from plasma consistent with a 2-compartment model of t½α = 5.7 min, a t½β = 1.3 h and a total clearance of 380 ml/min.Mean fibrinogen levels at the end of the infusions of 40 mg or 60 mg rt-PA over 90 min, measured in thawed plasma samples collected on citrate/aprotinin, decreased to 74% and 57% of the preinfusion values respectively. Plasminogen fell to 55% and 48%, and α2-antiplasmin to 28% and 18% of initial values. No further decrease of these parameters was observed during the infusion of 30 mg rt-PA over 6 h. Only 2% of the preinfusion fibrinogen levels could be recovered as fibrinogen-fibrin degradation products. This moderate extent of systemic fibrinogenolysis is much less than that reported for therapeutic i.v. infusions of streptokinase.

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