In-Silico Model for Predicting CYP2D6-Mediated Drug-Drug Interactions

2020 ◽  
Vol 15 ◽  
Author(s):  
Roberto Lozano ◽  
Alberto Frutos ◽  
Alejandro Martinez
Keyword(s):  
Drug Interaction ◽  
Therapeutic Range ◽  
Area Under Curve ◽  
Inhibitory Concentration ◽  
Mean Value ◽  
Inhibition Constant ◽  
Constant Ratio ◽  
The Mean

Background: Successful integration of in vitro into in vivo data on drug-drug interaction (DDI) is dependent on the inhibitory concentration used. Obtaining plasma concentration of a drug is only readily available for a small number of drugs in clinical practice, and so we propose the use of a therapeutic range as a substitute for inhibitory concentration. Objective: Because of this, we aimed to construct a linear-regression model based on the area-under-curve of the victim drugs and the therapeutic range, for a set of known inhibitors of the CYP2D6 of interest. Methods: Correlation analysis of linear log-log regression of two main variables: the area-under-curve ratio (AUCr) of the victim drugs and of the therapeutic range-to-inhibition constant ratio, with data obtained from literature. Results: Data were fitted to a linear log-log regression, between the average of the AUCr values and the mean value of the therapeutic range-to-inhibition constant ratio (TRm-to-Ki), of the inhibitory drugs. Conclusions: According to our results, knowledge of the inhibition constant and therapeutic range (or its plasma levels if disponible) of the inhibitor would be sufficient to determine the intensity and clinical relevance of a CYP2D6-mediated DDI.

scholarly journals Regression-Based Model for the Evaluation of CYP2D6-Mediated Drug-Drug Interactions

2020 ◽  
Author(s):  
Roberto Lozano ◽  
Alberto Frutos ◽  
Alberto Apesteguia ◽  
Alejandro Martinez ◽  
Maria-Angeles Alcazar ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Linear Regression ◽  
Drug Interactions ◽  
Regression Model ◽  
Area Under Curve ◽  
Mean Value ◽  
Inhibition Constant ◽  
Constant Ratio ◽  
The Mean ◽  
Inhibitory Drug

Linear regression-based model between area-under-curve (AUCr) and thetherapeutic range-to-inhibition constant ratio (TR-to-Ki). As result, a linear log-log regression model,between the averaged AUCr, calculated as the mean from the values of different DDIs between severalvictim-drugs with the same inhibitor (AUCr avg), and the mean TR-to-Ki ratio (TRm-to-Ki), calculated asthe mean value between the maximum and minimum TR of the inhibitor divided by its Ki, obtained thebest correlation (r2= 0.72; p=0.0116). Accordingly, a drug-drug interaction involving reversible inhibitorydrugs of CYP2D6 could be manage by adjusting dose of victim and/or inhibitory drug to the magnitudeof the desired change, by applying data of TR and Ki of inhibitor to the equation of regression linepresented here.

scholarly journals In Vitro Interactions of Artemisinin with Atovaquone, Quinine, and Mefloquine against Plasmodium falciparum

2002 ◽  
Vol 46 (5) ◽  
pp. 1510-1515 ◽  
Author(s):  
S. Gupta ◽  
M. M. Thapar ◽  
W. H. Wernsdorfer ◽  
A. Björkman
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Interaction ◽  
In Vitro Culture ◽  
Effective Concentration ◽  
Interstrain Differences ◽  
Molar Ratios ◽  
The Mean ◽  
In Vitro Interactions

ABSTRACT The interactions of artemisinin with atovaquone, quinine, and mefloquine were investigated in three Plasmodium falciparum strains (strains F-32, FCR-3, and K-1) by an in vitro culture assay. The parasites were cultured for 48 h in the presence of different concentrations and proportions of two drugs at a time in a checkerboard design. The response parameters were determined, and the sums of the fractional inhibitory concentrations (ΣFICs) of the drug combinations were calculated for different degrees of inhibition (50% effective concentration [EC50], EC90, and EC99). Within therapeutically relevant molar ratios (19 to 200), the combination of quinine and artemisinin showed mean ΣFICs of 1.71 at the EC50, 0.36 at the EC90, and 0.13 at the EC99, indicating increasing synergism. Within the range of molar ratios of 4.3 to 50, the combination of mefloquine and artemisinin yielded mean ΣFCIs of 0.93, 0.44, and 0.31 at the EC50, EC90, and EC99, respectively, indicating synergism. The atovaquone combination showed additive activity to synergism at atovaquone/artemisinin proportions considered relevant to the in vivo situation, i.e., between 4.3 and 200, with the mean ΣFICs decreasing from 1.34 at the EC50 to 0.85 and 0.23 at the EC90 and EC99, respectively. Interstrain differences in the degree of drug interaction were seen with the three strains for all combinations. Synergism was most consistent with quinine.

In Vitro and in Vivo Measurement of Total Antiplasmin Activity

1977 ◽  
Vol 37 (02) ◽  
pp. 216-221 ◽  
Author(s):  
Osamu Matsuo ◽  
Hisashi Mihara
Keyword(s):  
Plasma Volume ◽  
Fibrinolytic Activity ◽  
Mean Value ◽  
Rabbit Plasma ◽  
In Vivo Measurement ◽  
The Mean ◽  
Infusion Speed

SummaryTotal antiplasmin was measured in vitro and in vivo. In the former case, rabbit plasma was mixed with various concentrations of Urokinase (UK) and the least concentration for appearance of fibrinolytic activity was estimated. This concentration was multiplied by the plasma volume of the rabbit to give the in vitro total antiplasmin. The mean value for 14 rabbits was 4,068.6 units.In order to estimate the total antiplasmin in vivo, UK solution was infused into rabbits. The infusion speed was multiplied by the time of the first appearance of fibrinolytic activity to give the total antiplasmin, although when the infusion speed was low, fibrinolytic activity did not appear during infusion. The mean in vivo total antiplasmin calculated for 6 cases where the infusion speed was high and fibrinolytic activity was observed, was 28,699.8 units, i.e. about 7 (range, 3-11) times the in vitro value.

Assembly of three major subclasses of mouse immunoglobulin G: a theoretical model for covalent assembly in vivo

1976 ◽  
Vol 54 (8) ◽  
pp. 688-698 ◽  
Author(s):  
J. R. Percy ◽  
M. E. Percy ◽  
R. Baumal
Keyword(s):  
Cell Lines ◽  
Immunoglobulin G ◽  
Mean Value ◽  
Individual Values ◽  
In Vitro Assembly ◽  
The Mean ◽  
The Individual ◽  
Mouse Myeloma

A mathematical model, based on second-order reaction kinetics, has been used to describe the covalent assembly of immunoglobulin G (IgG) in vitro from its heavy (H) and light (L) chains (Percy, M. E., Baumal, R., Dorrington, K. J. &Percy, J. (1976) Can. J. Biochem. 54, 675–687). In the present paper, the same model has now been applied to the steady-state assembly of IgG in vivo. This mathematical approach permits a quantitative comparison of the pathways of covalent assembly used by given immunoglobulins in vivo and in vitro. The assumptions in the model are: the species L, H, HL, HH, HHL and LHHL belong to a common pool; incompleted IgG intermediates may freely assemble to form HL, HH, HHL and LHHL; the reaction rate for covalent linkage between any two reacting species is proportional to the products of the number densities of the reactants and to a parameter P which takes the value PHH if the reaction joins two H chains, and PHL if it joins an H and L chain. In vivo values of PHH/PHL were determined for the 18 mouse myeloma tumours and cell lines studied by Baumal et al. (Baumal, R., Potter, M. &Scharff, M. (1971) J. Exp. Med. 134, 1316–1334). From these analyses, we have arrived at the following conclusions: (1) the three major IgG subclasses have distinctive values of PHH/PHL (mean value 53 for IgG1, 12 for IgG2a and 2.8 for IgG2b); (2) for IgGs of the same subclass, the values of PHH/PHL are similar; (3) the mean in vivo values of PHH/PHL are very close to those determined from in vitro assembly experiments. Finally, the individual values of PHH/PHL have been used to simulate pulse-chase experiments in the various tumours and cell lines. Considering the sources and magnitude of experimental error, the theoretical pathways of assembly agree with those determined qualitatively from the pulse-chase experiments.

Blood Gases of the Tench (Tinca tinca) in Well Aerated and Oxygen-Deficient Waters

1974 ◽  
Vol 60 (1) ◽  
pp. 71-83 ◽  
Author(s):  
F. B. EDDY
Keyword(s):  
Venous Blood ◽  
Oxygen Affinity ◽  
Blood Gases ◽  
Mean Value ◽  
Hypoxic Conditions ◽  
Arterial Blood ◽  
The Mean ◽  
Tench Tinca Tinca

1. The respiration of tench at 13°C was investigated, particular attention being given to the role of the blood in uptake and transport of oxygen. 2. In well aerated water the mean value for arterial blood was 36 mmHg, for PCOCO2 3.3 mmHg and for pH 8.16; the respective venous values were 7 mmHg, 5 mmHg and 8.08. Arterial blood averaged about 75% and venous blood about 40° oxygen saturation. The mean value for oxygen uptake was 0.5 ml/min/kg and for ventilation volume 132/ml/mm/kg. 3. The oxygen tension and the percentage saturation of the blood determined in vivo are discussed in terms of the oxygen dissociation curve determined in vitro. 4. When the environmental POO2 was decreased, tench responded by increasing breathing rate and ventilation volume. Arterial POO2 and PCOCO2 decreased but arterial pH tended to remain steady. There was also a significant increase in blood lactate. 5. That tenth can withstand severe hypoxic conditions is attributed to blood of high oxygen affinity and the ability to maintain a favourable acid-base status in the blood for oxygen transport. 6. Respiration in tench is compared with that in other fish species.

scholarly journals ENZYME VARIATION, METABOLIC FLUX AND FITNESS: ALCOHOL DEHYDROGENASE IN DROSOPHILA MELANOGASTER

Genetics ◽  
1983 ◽  
Vol 105 (3) ◽  
pp. 633-650
Author(s):  
Richard J Middleton ◽  
Henrik Kacser
Keyword(s):  
Metabolic Flux ◽  
Mean Value ◽  
In Vivo Studies ◽  
Standard Errors ◽  
In Vitro Activity ◽  
Enzyme Variation ◽  
Flux Level ◽  
The Mean

ABSTRACT Although there are many in vitro studies of enzyme activity of genetic variants at the Adh locus in D. melanogaster, little is known about the corresponding metabolic activity in living flies. We report here such measurements of the metabolic flux in the conversion of ethanol to the two products, CO2 and lipids, for six different active genotypes, containing the predominant naturally recurring alleles and covering a threefold range of in vitro activity. In adult flies we have found nonsignificant differences between genotypes in metabolic flux when estimates for individual genotypes had standard errors of approximately 10% of the mean value. In vitro activities are, therefore, poor predictors of the physiological consequences of enzyme variation since such determinations ignore the interactions inherent in multienzyme systems. We have no evidence that heterozygote show overdominance either at the enzyme or the flux level. Since fitness differences between genotypes must be generated by physiological differences, investigations of polymorphisms should be based on in vivo studies.

Reliability of a Single β-Thromboglobulin Measurement in a Diabetic Population : Importance of PGE1 in Anticoagulant Mixture

1987 ◽  
Vol 57 (02) ◽  
pp. 201-204 ◽  
Author(s):  
P Y Scarabin ◽  
L Strain ◽  
C A Ludlam ◽  
J Jones ◽  
E M Kohner
Keyword(s):  
In Vitro Release ◽  
Mean Value ◽  
Reliable Estimate ◽  
Diabetic Patients ◽  
Single Measurement ◽  
Diabetic Population ◽  
The Difference ◽  
Vitro Release

SummaryDuring the collection of samples for plasma β-thromboglobulin (β-TG) determination, it is well established that artificially high values can be observed due to in-vitro release. To estimate the reliability of a single β-TG measurement, blood samples were collected simultaneously from both arms on two separate occasions in 56 diabetic patients selected for a clinical trial. From each arm, blood was taken into two tubes containing an anticoagulant mixture with (tube A) and without (tube B) PGE!. The overall mean value of B-TG in tube B was 1.14 times higher than in tube A (p <0.01). The markedly large between-arms variation accounted for the most part of within-subject variation in both tubes and was significantly greater in tube B than in tube A. Based on the difference between B-TG values from both arms, the number of subjects with artifically high B-TG values was significantly higher in tube B than in tube A on each occasion (overall rate: 28% and 14% respectively). Estimate of between-occasions variation showed that B-TG levels were relatively stable for each subject between two occasions in each tube. It is concluded that the use of PGEi decreases falsely high B-TG levels, but a single measurement of B-TG does not provide a reliable estimate of the true B-TG value in vivo.

Influence of Platelet Membrane Sialic Acid and Platelet-Associated IgG on Ageing and Sequestration of Blood Platelets in Baboons

1993 ◽  
Vol 70 (04) ◽  
pp. 676-680 ◽  
Author(s):  
H F Kotzé ◽  
V van Wyk ◽  
P N Badenhorst ◽  
A du P Heyns ◽  
J P Roodt ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Life Span ◽  
Blood Platelets ◽  
Senescent Cell ◽  
Platelet Membrane ◽  
Antigen Complex ◽  
The Mean ◽  
Aggregation Of Platelets

SummaryPlatelets were isolated from blood of baboons and treated with neuraminidase to remove platelet membrane sialic acid, a process which artificially ages the platelets. The platelets were then labelled with 111In and their mean life span, in vivo distribution and sites of Sequestration were measured. The effect of removal of sialic acid on the attachment of immunoglobulin to platelets were investigated and related to the Sequestration of the platelets by the spleen, liver, and bone marrow. Removal of sialic acid by neuraminidase did not affect the aggregation of platelets by agonists in vitro, nor their sites of Sequestration. The removal of 0.51 (median, range 0.01 to 2.10) nmol sialic acid/108 platelets shortened their life span by 75 h (median, range 0 to 132) h (n = 19, p <0.001), and there was an exponential correlation between the shortening of the mean platelet life span and the amount of sialic acid removed. The increase in platelet-associated IgG was 0.112 (median, range 0.007 to 0.309) fg/platelet (n = 25, p <0.001) after 0.79 (median, range 0.00 to 6.70) nmol sialic acid/108 platelets was removed (p <0.001). There was an exponential correlation between the shortening of mean platelet life span after the removal of sialic acid and the increase in platelet-associated IgG. The results suggest that platelet membrane sialic acid influences ageing of circulating platelets, and that the loss of sialic acid may have exposed a senescent cell antigen that binds IgG on the platelet membrane. The antibody-antigen complex may then provide a signal to the macrophages that the platelet is old, and can be phagocytosed and destroyed.

scholarly journals Formulation and in vitro evaluation of self-nanoemulsifying liquisolid tablets of furosemide

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lena Dalal ◽  
Abdul Wahab Allaf ◽  
Hind El-Zein
Keyword(s):  
Theoretical Model ◽  
Castor Oil ◽  
In Vivo Studies ◽  
Coating Materials ◽  
Peg 400 ◽  
The Mean ◽  
Usp Apparatus ◽  
Solid System

AbstractSelf-nanoemulsifying drug delivery systems (SNEDDS) were used to enhance the dissolution rate of furosemide as a model for class IV drugs and the system was solidified into liquisolid tablets. SNEDDS of furosemide contained 10% Castor oil, 60% Cremophor EL, and 30% PEG 400. The mean droplets size was 17.9 ± 4.5 nm. The theoretical model was used to calculate the amounts of the carrier (Avicel PH101) and coating materials (Aerosil 200) to prepare liquisolid powder. Carrier/coating materials ratio of 5/1 was used and Ludipress was added to the solid system, thus tablets with hardness of 45 ± 2 N were obtained. Liquisolid tablets showed 2-folds increase in drug release as compared to the generic tablets after 60 min in HCl 0.1 N using USP apparatus-II. Furosemide loaded SNEDDS tablets have great prospects for further in vivo studies, and the theoretical model is useful for calculating the adequate amounts of adsorbents required to solidify these systems.

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