Computational models were used to evaluate controlled release oral delivery of three gamma-carboline antipsychotic compounds. In vitro and rat studies showed one compound (B) was well absorbed in both the upper and lower GI tract. Dog studies also showed similar absorption profiles for compound B in both regions. Modeling predicted that controlled release delivery of compound B could achieve quasi-steady plasma concentrations above the threshold for efficacy for longer than immediate release delivery, potentially allowing once-daily dosing. Controlled release was thus found to be a feasible approach for compound B to extend duration of action.
This document describes a study analyzing benzo(a)pyrene (BaP) and its metabolites in biological samples using high performance liquid chromatography with fluorescence detection and gas chromatography mass spectrometry. The researchers developed a sensitive method to detect and quantify BaP and four of its hydroxylated metabolites (1-OHBaP, 3-OHBaP, 4,5-diolBaP, and 7,8-diolBaP) in rat urine and plasma. They found that derivatization of the metabolites with alkyl iodide improved their resolution and detection, allowing separation of 1-OHBaP and 3-OHBaP which previously co-eluted. The method was validated and successfully
This document describes a method for simultaneously determining the concentrations of levodopa, carbidopa, and their metabolites in human plasma and urine samples using liquid chromatography with electrochemical detection (LC-EC). The method involves online sample clean-up and enrichment using a switching valve and pre-column. Several interfering endogenous compounds are eliminated, allowing for the sensitive and selective quantification of the target analytes. Recovery studies on human plasma samples showed good accuracy and precision. The method is simple, inexpensive, and suitable for routine analysis and kinetic studies of these important drugs and their metabolites.
This document describes a structure-activity relationship study of N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides as potassium channel openers (PCOs) that activate ATP-sensitive potassium channels (KATP). Compounds 39, 41, and 64 were found to be non-antiandrogen KATP openers that showed selectivity for the bladder over cardiovascular effects in rats. Modifications to the aryl rings of 41 and 64 gave derivatives with similar bladder selectivity. Compounds 41 and 64 were resolved into their enantiomers, with PCO activity residing in the (S)-enantiomers. ZD6169 (41(S)) was selected
Structural proteomics of glutathionylation and glycation of erythrocyte prote...Monita Muralidharan
Glutathionylated and glycated hemoglobin were characterized through structural proteomics. Hydrogen/deuterium exchange kinetics showed that glutathionylation caused significant structural changes and increased flexibility in several regions of the globin chains compared to normal hemoglobin. Collision cross-section measurements by ion mobility-mass spectrometry indicated the collisional cross-section of glutathionylated hemoglobin was smaller than normal hemoglobin. Oxygen dissociation curves demonstrated glutathionylated hemoglobin had lower oxygen affinity than normal hemoglobin. Glycation sites on hemoglobin were identified by mass spectrometry as the N-terminal peptide of the beta chain, with a mass increase of 162 Da.
This document summarizes a study that analyzed the kinetics of proton transport by the M2 protein channel from influenza A virus. The researchers found that proton flux through M2 follows Michaelis-Menten kinetics with two saturation steps around pH 5.5 and pH 4. They determined rate constants and apparent pKa values that matched the pKa values of the histidine residues in M2 that were previously observed. Mutagenesis studies identified residues important for proton entrance, relay, and exit rates. NMR experiments showed synchronized conformational changes between the histidine and tryptophan gate residues during activation.
This study examined the individual metabolism of apolipoprotein (a) [apo(a)] and apolipoprotein B-100 [apoB-100] within lipoprotein (a) [Lp(a)] particles in the blood. Researchers found that the rate at which apo(a) is cleared from the blood is about half the rate at which apoB-100 is cleared when using an immunoprecipitation method to separate the proteins, whereas earlier studies found similar clearance rates using ultracentrifugation. The differences in clearance rates depending on the separation technique suggest that apo(a) and apoB-100 within Lp(a) particles may not be catabolized together in the non-fasting state. The study helps
The document reports on the synthesis and characterization of diruthenium complexes with mixed anionic bridging ligands. Key findings include:
- Reaction time affects product yield, with intermediates having fewer acetate ligands favored kinetically.
- X-ray crystal structures of Ru2(ac)2(ap)2Cl and Ru2(ac)2(Fap)2Cl show the bridging ligands adopt a trans configuration after acetate substitution. Bond lengths and angles provide insight into electronic vs. steric effects.
- Electrochemical studies show redox processes shift negatively with increased electron density from acetate substitution. The HOMO-LUMO gap decreases more for complexes with more Fap ligands.
This document describes a study analyzing benzo(a)pyrene (BaP) and its metabolites in biological samples using high performance liquid chromatography with fluorescence detection and gas chromatography mass spectrometry. The researchers developed a sensitive method to detect and quantify BaP and four of its hydroxylated metabolites (1-OHBaP, 3-OHBaP, 4,5-diolBaP, and 7,8-diolBaP) in rat urine and plasma. They found that derivatization of the metabolites with alkyl iodide improved their resolution and detection, allowing separation of 1-OHBaP and 3-OHBaP which previously co-eluted. The method was validated and successfully
This document describes a method for simultaneously determining the concentrations of levodopa, carbidopa, and their metabolites in human plasma and urine samples using liquid chromatography with electrochemical detection (LC-EC). The method involves online sample clean-up and enrichment using a switching valve and pre-column. Several interfering endogenous compounds are eliminated, allowing for the sensitive and selective quantification of the target analytes. Recovery studies on human plasma samples showed good accuracy and precision. The method is simple, inexpensive, and suitable for routine analysis and kinetic studies of these important drugs and their metabolites.
This document describes a structure-activity relationship study of N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides as potassium channel openers (PCOs) that activate ATP-sensitive potassium channels (KATP). Compounds 39, 41, and 64 were found to be non-antiandrogen KATP openers that showed selectivity for the bladder over cardiovascular effects in rats. Modifications to the aryl rings of 41 and 64 gave derivatives with similar bladder selectivity. Compounds 41 and 64 were resolved into their enantiomers, with PCO activity residing in the (S)-enantiomers. ZD6169 (41(S)) was selected
Structural proteomics of glutathionylation and glycation of erythrocyte prote...Monita Muralidharan
Glutathionylated and glycated hemoglobin were characterized through structural proteomics. Hydrogen/deuterium exchange kinetics showed that glutathionylation caused significant structural changes and increased flexibility in several regions of the globin chains compared to normal hemoglobin. Collision cross-section measurements by ion mobility-mass spectrometry indicated the collisional cross-section of glutathionylated hemoglobin was smaller than normal hemoglobin. Oxygen dissociation curves demonstrated glutathionylated hemoglobin had lower oxygen affinity than normal hemoglobin. Glycation sites on hemoglobin were identified by mass spectrometry as the N-terminal peptide of the beta chain, with a mass increase of 162 Da.
This document summarizes a study that analyzed the kinetics of proton transport by the M2 protein channel from influenza A virus. The researchers found that proton flux through M2 follows Michaelis-Menten kinetics with two saturation steps around pH 5.5 and pH 4. They determined rate constants and apparent pKa values that matched the pKa values of the histidine residues in M2 that were previously observed. Mutagenesis studies identified residues important for proton entrance, relay, and exit rates. NMR experiments showed synchronized conformational changes between the histidine and tryptophan gate residues during activation.
This study examined the individual metabolism of apolipoprotein (a) [apo(a)] and apolipoprotein B-100 [apoB-100] within lipoprotein (a) [Lp(a)] particles in the blood. Researchers found that the rate at which apo(a) is cleared from the blood is about half the rate at which apoB-100 is cleared when using an immunoprecipitation method to separate the proteins, whereas earlier studies found similar clearance rates using ultracentrifugation. The differences in clearance rates depending on the separation technique suggest that apo(a) and apoB-100 within Lp(a) particles may not be catabolized together in the non-fasting state. The study helps
The document reports on the synthesis and characterization of diruthenium complexes with mixed anionic bridging ligands. Key findings include:
- Reaction time affects product yield, with intermediates having fewer acetate ligands favored kinetically.
- X-ray crystal structures of Ru2(ac)2(ap)2Cl and Ru2(ac)2(Fap)2Cl show the bridging ligands adopt a trans configuration after acetate substitution. Bond lengths and angles provide insight into electronic vs. steric effects.
- Electrochemical studies show redox processes shift negatively with increased electron density from acetate substitution. The HOMO-LUMO gap decreases more for complexes with more Fap ligands.
SIMONA CAVALU_Raman and surface-enhanced Raman spectroscopy of tempyo spin la...Simona Cavalu
Tempyo labelled ovalbumin at different pH values was prepared and investigated using Raman and SERS spectroscopy.
Raman spectra of tempyo labelled ovalbumin in the pH range from 6.7 to 11 were compared to those of the corresponding free
ovalbumin. In the basic pH range from 6.7 to 11 the molecular conformation was found to be unaffected by the tempyo
presence. Adsorption versatility to the colloidal Ag particles of pure- and tempyo labelled ovalbumin was also found to be
unchanged in this basic pH range. As the SERS binding site of protein the a-helix conformation is favourable.
Poster demonstrating the results from the development/verification project for the quantitation of pyridoxal 5-phosphate and 4-pyridoxic acid in human plasma.
IRJET- Kinetic Study of the Reaction of 5-Chlorosalicyaldehyde with M- To...IRJET Journal
This document reports on a kinetic study of the reaction between 5-chlorosalicylaldehyde and m-toluidine to form a Schiff base. The reaction was studied spectrophotometrically in ethanol solution at temperatures ranging from 303 to 318 K. The reaction was found to be first order with respect to both 5-chlorosalicylaldehyde and m-toluidine. The rate of reaction increased with increasing temperature. Thermodynamic parameters including activation energy, enthalpy, entropy and free energy were calculated from the temperature dependence of the reaction rate.
This document provides an overview of renal physiology. It discusses the major topics of body fluid compartments, the functional anatomy of the kidney, and basic renal mechanisms including glomerular filtration, tubular reabsorption, and tubular secretion. Glomerular filtration typically filters around 180 liters of fluid per day, while only 1-2 liters are excreted as urine through reabsorption in the tubules. Tubular reabsorption conserves essential substances like water, glucose, electrolytes, and bicarbonate that were filtered at the glomerulus. The kidney regulates fluid and solute balance through these complex and highly integrated filtration, reabsorption, and secretory processes.
Nalbuphine hydrochloride (5a,6a)-17-(Cyclobutylmethyl)-4,5- epoxymorphinan-3,6,14-triol hydrochloride, is narcotic analgesic drug which is a morphine- like drug with agonist activity at the k- opioid receptor and antagonist activity at the μ-opioid receptor. Nalbuphine is recommended for use in moderate to serve pain and its indications include pain after myocardial infraction.
Cooperative learning in science education is addressed in this article. How students use a very relevant topic of anti-cancer agents, and the novel technique of (Heteronuclear single Quantum Correllation Spectroscopy )2D -HSQC FT-NMR to organize spectra data is shown. Here, undergraduates become familiar with making plots of 1H FT-NMR and 13C FT-NMR , learning FT-NMR data processing (spinworks) and also use Chemdraw NMR to present data take with a Varian 600 MHz FT-NMR spectrometer.
The document describes the complementarity plot (CP), a validation tool for protein structures based on packing and electrostatics of buried residues. The CP plots surface complementarity against electrostatic complementarity for buried residues. The document outlines how local and global scores are designed based on the CP to detect various errors, such as incorrect side chain orientations, diffuse main chain errors, and imbalanced charges. Validation results show the CP is effective at discriminating obsolete structures from updated ones and identifying other errors. Applications of the CP in protein modeling and design are also demonstrated.
Design of ultrasensitive DNA-based fluorescent pH sensitive nanodevices_MSsaheli halder
This document describes the design of new DNA-based fluorescent nanodevices that act as pH sensors with expanded sensitivity. The nanodevices use DNA i-motifs that undergo a conformational change between an i-motif structure at acidic pH and a duplex structure at basic pH. By incorporating chemically modified cytosines into the i-motif region, the researchers were able to tune the pH sensitivity range of the nanodevices. They created versions with brominated or methylated cytosines in different positions, and found that some achieved a collective sensing range from pH 5.3 to 7.5. The modified nanodevices also exhibited much larger signal changes between the two conformations, resulting in improved dynamic range for pH sensing.
1. The document discusses bioavailability and bioequivalence studies, which are important for determining the rate and extent of drug absorption from different formulations.
2. Key aspects of bioavailability studies include absolute and relative bioavailability, factors affecting bioavailability, and methods of measuring bioavailability through pharmacokinetic and pharmacodynamic approaches.
3. Bioequivalence studies aim to show that two products have identical plasma concentration time profiles and are therefore interchangeable. Different study designs like randomized and crossover designs are used to evaluate bioequivalence.
Martinez use of in silico models to support canine drug developmentCertara
The FDA's Dr. Marilyn Martinez discusses how biosimulation based approaches, such as PBPK modeling, can support developing safer, more effective medications for dogs.
Extrapolation of preclinical data to clinical data.pptxVincyDinakaran
EXTRAPOLATION OF PRECLINICAL DATA TO CLINICAL DATA
EXTRAPOLATION
It is the prediction of effects in humans from effects in animals using pharmacokinetics and pharmacodynamics studies.
Extrapolation of drug dose or pharmacokinetic parameter to a species of interest is called scaling.
Scaling is of two types:
ISOMETRIC SCALING – dose for one species is applied to all
ALLOMETRIC SCALING – correlating mass of an organism with physiological parameters
ALLOMETRIC SCALING
It was a technique developed to explain the observed relationship between organ size and body weight of mammals.
Allometric scaling of pharmacokinetic data typically focus on interspecies relationship between clearance and volume of distribution of unbound drug and species body weight. These are then extrapolated to humans.
DISADVANTAGES
Purely empirical.
Cannot give any idea about the mechanism of action.
PBPK (Physiology based pharmacokinetic) modelling
It make use of data such as prediction of clearance and tissue distribution from in- vitro and in-silico data.
It is useful in predicting plasma and tissue concentration time profiles.
Also useful in addressing issues in pharmacokinetics (eg: saturable metabolism) and inter-species differences in nature, expression levels and dissipation of pharmacological effects.
NEW METHODS OF PREDICTING PHARMACOKINETICS
Methods for predicting human volume of distribution
Methods for predicting human clearance
Methods for predicting human t ½
Methods for predicting human oral bioavailability
Methods for predicting human volume of distribution
● Average fraction unbound in tissue method
● Proportionality
● Allometry without protein binding
● Allometry corrected for protein binding
a. Average fraction unbound in tissue
Uses experimentally determined value for volume of distribution and plasma protein binding for each species , along with standard values for extracellular fluid volumes , plasma volumes and calculate the fraction unbound in tissues in animal species
Fut = Vr Fu
[VDss – Vp (Fu Ve)] – [(1-Fu)(Re/i)Vp]
Avg Fut of different species is calculated and averaged.
Average will be equal to human Fut
Experimentally determine human Fu
VD(human prediction)= Vp+ [Fu(human) x Ve] + {[1-Fu(human) ]x (Re/i)x Vp} +Vr {Fu(human) / Fut(avg) }
b. Proportionality Method
Proportionality could be setup between the fraction of drug in plasma in dog and the human and the volume of distribution in these 2 species.
The assumption was that the tissue binding of drug is similar in dogs and humans and that physiological parameters such as extracellular fluid volumes are similar between the 2 species.
VD (human prediction) = Fu(human). VD(dog)
Fu(dog)
Fu – fraction of unbound drug in the plasma of dog and human
VD(dog) –volume of distribution at steady state in dog
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
IN-VITRO-IN VIVO CORRELATION (IVIVC).pptxRAHUL PAL
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
Computational modelling of drug disposition active transportSUJITHA MARY
This document discusses computational modeling of active transport mechanisms that influence drug disposition. It summarizes modeling efforts for several major drug transporters, including P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), nucleoside transporters, peptide transporter 1 (hPEPT1), Apical Sodium-dependent Bile Acid Transporter (ASBT), Organic Cation Transporters (OCTs), Organic Anion Transporting Polypeptides (OATPs), and the Blood Brain Barrier choline transporter. While transporter modeling has advanced, fully incorporating active transport into predictive models remains an ongoing challenge.
Theoretical background on GastroPlus Simulation SoftwareArpitha Aarushi
this slides tells about Theoretical background on GastroPlus Simulation Software, basic ACAT model, and schematic diagram of compartment and sub compartment model.
Seahorse Poster DOS (JJW Edits 6-15-15)Zach Swanson
The study compared measurements of oxygen consumption rate (OCR) in pancreatic islets from pigs and non-human primates using an extracellular flux analyzer and a stirred microchamber method. The analyzer produced comparable OCR measurements to the standard method but with higher variability. Basal OCR was lower in non-human primate islets than pig islets, but primate islets showed a greater increase in OCR in response to hyperglycemia. Immature pig islets had almost no OCR response to glucose. The analyzer can provide species-specific and maturation state insights into islet function and mitochondrial health beyond what the standard method allows.
This document summarizes computational models of active transporters involved in drug disposition. It discusses models developed for P-gp, BCRP, nucleoside transporters, hPEPT1, ASBT, OCT, OATP, and the BBB choline transporter. The models were generated using techniques like pharmacophore modeling and QSAR to identify structural features important for substrate recognition and transport by each protein, which can help predict drug absorption, distribution, and excretion. The document provides details on specific structural requirements identified for several important transporters from the models.
The document discusses in-vitro in-vivo correlation (IVIVC) which relates the dissolution of a drug from a dosage form to its absorption in vivo. It provides different levels or stages of IVIVC from simple point-to-point correlations to more complex models incorporating pharmacokinetic parameters. Common dissolution models are also summarized, including zero-order, first-order, Hixson-Crowell, and Higuchi models. Establishing IVIVC can help reduce bioequivalence studies and ensure consistent performance of drug products.
Computational modelling of drug disposition lalitajoshi9
computational modelling of drug disposition is the integral part of computer aided drug design. different kinds of tools being used in the prediction of drug disposition in human body. This topic in the CADD explains the details about the drug disposition, active transporters and tools.
SIMONA CAVALU_Raman and surface-enhanced Raman spectroscopy of tempyo spin la...Simona Cavalu
Tempyo labelled ovalbumin at different pH values was prepared and investigated using Raman and SERS spectroscopy.
Raman spectra of tempyo labelled ovalbumin in the pH range from 6.7 to 11 were compared to those of the corresponding free
ovalbumin. In the basic pH range from 6.7 to 11 the molecular conformation was found to be unaffected by the tempyo
presence. Adsorption versatility to the colloidal Ag particles of pure- and tempyo labelled ovalbumin was also found to be
unchanged in this basic pH range. As the SERS binding site of protein the a-helix conformation is favourable.
Poster demonstrating the results from the development/verification project for the quantitation of pyridoxal 5-phosphate and 4-pyridoxic acid in human plasma.
IRJET- Kinetic Study of the Reaction of 5-Chlorosalicyaldehyde with M- To...IRJET Journal
This document reports on a kinetic study of the reaction between 5-chlorosalicylaldehyde and m-toluidine to form a Schiff base. The reaction was studied spectrophotometrically in ethanol solution at temperatures ranging from 303 to 318 K. The reaction was found to be first order with respect to both 5-chlorosalicylaldehyde and m-toluidine. The rate of reaction increased with increasing temperature. Thermodynamic parameters including activation energy, enthalpy, entropy and free energy were calculated from the temperature dependence of the reaction rate.
This document provides an overview of renal physiology. It discusses the major topics of body fluid compartments, the functional anatomy of the kidney, and basic renal mechanisms including glomerular filtration, tubular reabsorption, and tubular secretion. Glomerular filtration typically filters around 180 liters of fluid per day, while only 1-2 liters are excreted as urine through reabsorption in the tubules. Tubular reabsorption conserves essential substances like water, glucose, electrolytes, and bicarbonate that were filtered at the glomerulus. The kidney regulates fluid and solute balance through these complex and highly integrated filtration, reabsorption, and secretory processes.
Nalbuphine hydrochloride (5a,6a)-17-(Cyclobutylmethyl)-4,5- epoxymorphinan-3,6,14-triol hydrochloride, is narcotic analgesic drug which is a morphine- like drug with agonist activity at the k- opioid receptor and antagonist activity at the μ-opioid receptor. Nalbuphine is recommended for use in moderate to serve pain and its indications include pain after myocardial infraction.
Cooperative learning in science education is addressed in this article. How students use a very relevant topic of anti-cancer agents, and the novel technique of (Heteronuclear single Quantum Correllation Spectroscopy )2D -HSQC FT-NMR to organize spectra data is shown. Here, undergraduates become familiar with making plots of 1H FT-NMR and 13C FT-NMR , learning FT-NMR data processing (spinworks) and also use Chemdraw NMR to present data take with a Varian 600 MHz FT-NMR spectrometer.
The document describes the complementarity plot (CP), a validation tool for protein structures based on packing and electrostatics of buried residues. The CP plots surface complementarity against electrostatic complementarity for buried residues. The document outlines how local and global scores are designed based on the CP to detect various errors, such as incorrect side chain orientations, diffuse main chain errors, and imbalanced charges. Validation results show the CP is effective at discriminating obsolete structures from updated ones and identifying other errors. Applications of the CP in protein modeling and design are also demonstrated.
Design of ultrasensitive DNA-based fluorescent pH sensitive nanodevices_MSsaheli halder
This document describes the design of new DNA-based fluorescent nanodevices that act as pH sensors with expanded sensitivity. The nanodevices use DNA i-motifs that undergo a conformational change between an i-motif structure at acidic pH and a duplex structure at basic pH. By incorporating chemically modified cytosines into the i-motif region, the researchers were able to tune the pH sensitivity range of the nanodevices. They created versions with brominated or methylated cytosines in different positions, and found that some achieved a collective sensing range from pH 5.3 to 7.5. The modified nanodevices also exhibited much larger signal changes between the two conformations, resulting in improved dynamic range for pH sensing.
1. The document discusses bioavailability and bioequivalence studies, which are important for determining the rate and extent of drug absorption from different formulations.
2. Key aspects of bioavailability studies include absolute and relative bioavailability, factors affecting bioavailability, and methods of measuring bioavailability through pharmacokinetic and pharmacodynamic approaches.
3. Bioequivalence studies aim to show that two products have identical plasma concentration time profiles and are therefore interchangeable. Different study designs like randomized and crossover designs are used to evaluate bioequivalence.
Martinez use of in silico models to support canine drug developmentCertara
The FDA's Dr. Marilyn Martinez discusses how biosimulation based approaches, such as PBPK modeling, can support developing safer, more effective medications for dogs.
Extrapolation of preclinical data to clinical data.pptxVincyDinakaran
EXTRAPOLATION OF PRECLINICAL DATA TO CLINICAL DATA
EXTRAPOLATION
It is the prediction of effects in humans from effects in animals using pharmacokinetics and pharmacodynamics studies.
Extrapolation of drug dose or pharmacokinetic parameter to a species of interest is called scaling.
Scaling is of two types:
ISOMETRIC SCALING – dose for one species is applied to all
ALLOMETRIC SCALING – correlating mass of an organism with physiological parameters
ALLOMETRIC SCALING
It was a technique developed to explain the observed relationship between organ size and body weight of mammals.
Allometric scaling of pharmacokinetic data typically focus on interspecies relationship between clearance and volume of distribution of unbound drug and species body weight. These are then extrapolated to humans.
DISADVANTAGES
Purely empirical.
Cannot give any idea about the mechanism of action.
PBPK (Physiology based pharmacokinetic) modelling
It make use of data such as prediction of clearance and tissue distribution from in- vitro and in-silico data.
It is useful in predicting plasma and tissue concentration time profiles.
Also useful in addressing issues in pharmacokinetics (eg: saturable metabolism) and inter-species differences in nature, expression levels and dissipation of pharmacological effects.
NEW METHODS OF PREDICTING PHARMACOKINETICS
Methods for predicting human volume of distribution
Methods for predicting human clearance
Methods for predicting human t ½
Methods for predicting human oral bioavailability
Methods for predicting human volume of distribution
● Average fraction unbound in tissue method
● Proportionality
● Allometry without protein binding
● Allometry corrected for protein binding
a. Average fraction unbound in tissue
Uses experimentally determined value for volume of distribution and plasma protein binding for each species , along with standard values for extracellular fluid volumes , plasma volumes and calculate the fraction unbound in tissues in animal species
Fut = Vr Fu
[VDss – Vp (Fu Ve)] – [(1-Fu)(Re/i)Vp]
Avg Fut of different species is calculated and averaged.
Average will be equal to human Fut
Experimentally determine human Fu
VD(human prediction)= Vp+ [Fu(human) x Ve] + {[1-Fu(human) ]x (Re/i)x Vp} +Vr {Fu(human) / Fut(avg) }
b. Proportionality Method
Proportionality could be setup between the fraction of drug in plasma in dog and the human and the volume of distribution in these 2 species.
The assumption was that the tissue binding of drug is similar in dogs and humans and that physiological parameters such as extracellular fluid volumes are similar between the 2 species.
VD (human prediction) = Fu(human). VD(dog)
Fu(dog)
Fu – fraction of unbound drug in the plasma of dog and human
VD(dog) –volume of distribution at steady state in dog
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
IN-VITRO-IN VIVO CORRELATION (IVIVC).pptxRAHUL PAL
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
Computational modelling of drug disposition active transportSUJITHA MARY
This document discusses computational modeling of active transport mechanisms that influence drug disposition. It summarizes modeling efforts for several major drug transporters, including P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), nucleoside transporters, peptide transporter 1 (hPEPT1), Apical Sodium-dependent Bile Acid Transporter (ASBT), Organic Cation Transporters (OCTs), Organic Anion Transporting Polypeptides (OATPs), and the Blood Brain Barrier choline transporter. While transporter modeling has advanced, fully incorporating active transport into predictive models remains an ongoing challenge.
Theoretical background on GastroPlus Simulation SoftwareArpitha Aarushi
this slides tells about Theoretical background on GastroPlus Simulation Software, basic ACAT model, and schematic diagram of compartment and sub compartment model.
Seahorse Poster DOS (JJW Edits 6-15-15)Zach Swanson
The study compared measurements of oxygen consumption rate (OCR) in pancreatic islets from pigs and non-human primates using an extracellular flux analyzer and a stirred microchamber method. The analyzer produced comparable OCR measurements to the standard method but with higher variability. Basal OCR was lower in non-human primate islets than pig islets, but primate islets showed a greater increase in OCR in response to hyperglycemia. Immature pig islets had almost no OCR response to glucose. The analyzer can provide species-specific and maturation state insights into islet function and mitochondrial health beyond what the standard method allows.
This document summarizes computational models of active transporters involved in drug disposition. It discusses models developed for P-gp, BCRP, nucleoside transporters, hPEPT1, ASBT, OCT, OATP, and the BBB choline transporter. The models were generated using techniques like pharmacophore modeling and QSAR to identify structural features important for substrate recognition and transport by each protein, which can help predict drug absorption, distribution, and excretion. The document provides details on specific structural requirements identified for several important transporters from the models.
The document discusses in-vitro in-vivo correlation (IVIVC) which relates the dissolution of a drug from a dosage form to its absorption in vivo. It provides different levels or stages of IVIVC from simple point-to-point correlations to more complex models incorporating pharmacokinetic parameters. Common dissolution models are also summarized, including zero-order, first-order, Hixson-Crowell, and Higuchi models. Establishing IVIVC can help reduce bioequivalence studies and ensure consistent performance of drug products.
Computational modelling of drug disposition lalitajoshi9
computational modelling of drug disposition is the integral part of computer aided drug design. different kinds of tools being used in the prediction of drug disposition in human body. This topic in the CADD explains the details about the drug disposition, active transporters and tools.
The aim of the use of meloxicam in patients with mild or moMUSHTAQ AHMED
This document summarizes several studies on the pharmacokinetics of the drug meloxicam. It finds that meloxicam has a half-life of around 20 hours, making it suitable for once-daily dosing. It is metabolized into inactive metabolites that are excreted in urine and feces. The pharmacokinetic profile in rats most closely resembles that in humans. Studies also show that dosage adjustment is not needed for meloxicam in patients with mild to moderate renal impairment or in the elderly.
Myself Omkar Tipugade , M - Pharm sem II , department of Pharmaceutics , today will upload presentation on Computational modeling in drug disposition .
The document describes a study that used a Caco-2 cell line model to investigate the intestinal absorption mechanism of carvedilol-loaded solid lipid nanoparticles (SLNs). Optimized carvedilol-loaded SLNs were prepared and characterized. The Caco-2 cell line was then used to study the effect of SLN concentration and incubation time on cellular uptake. Pretreatments were applied to the cells, which were then treated with SLNs, a physical mixture control, or a carvedilol solution. The results suggest the main absorption mechanism for the SLNs is endocytosis, specifically clathrin-mediated endocytosis. When a Transwell permeable support was used, the mechanism for SLNs was determined to be carrier
Computational modeling in drug dispositionHimal Barakoti
The document discusses computational modeling of drug disposition. It covers modeling of drug absorption, distribution, excretion, and active transport. For drug absorption, it describes modeling of solubility, intestinal permeability, and transporters involved. It also discusses modeling approaches for distribution processes like volume of distribution, plasma protein binding, and blood-brain barrier permeability. Current challenges include better incorporating the effects of active transporters in models. The document emphasizes that while computational models are useful for predicting drug properties, fully accounting for complex biological factors remains difficult.
Evaluation of the chronic kidney disease epidemiology 2010eduardo de avila
This study evaluated differences in estimated glomerular filtration rate (GFR) and antimicrobial dosing recommendations when using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation versus the Cockcroft-Gault equation in patients with chronic kidney disease. The CKD-EPI equation estimated higher average GFRs compared to the Cockcroft-Gault equation. There was a 15-25% discordance rate in antimicrobial dosing recommendations between the two equations. While the equations showed statistically significant differences, the clinical significance of these differences in patient outcomes is uncertain. Clinical judgment should be used when making renal dosage adjustments of antimicrobials.
Similar to CRS 2005 - ADME-PK anti-psychotics (20)
Evaluation of the chronic kidney disease epidemiology 2010
CRS 2005 - ADME-PK anti-psychotics
1. Computational Evaluation of Controlled Release Oral Delivery for Some Atypical Antipsychotics
GM Eichenbaum, VA Nguyen and WW van Osdol
ALZA Corporation, Mountain View, CA 94043
bvanosdo@alzus.jnj.com
Abstract Summary
We use computational ADME tools, physical
chemical measurements in vitro, and the results of site-
specific gastrointestinal dosing in the rat and dog to
predict the effect of controlled release oral delivery on
the plasma concentrations and duration of action of a
series of -carboline atypical antipsychotics.
Introduction
Historically, controlled release drug delivery
technologies have been applied to rescue or improve
marketed drugs and late stage clinical candidates.
However, controlled release (CR) drug delivery could
also offer an approach for reducing attrition of
compounds advancing from the lead optimization stage of
drug discovery. Drug discovery has generally not
considered CR drug delivery approaches at the lead
optimization stage, focusing instead on synthesizing
compounds that are suitable for immediate release (IR)
oral delivery. Compounds identified during lead
optimization that subsequently prove to be unsuitable for
IR oral delivery rarely advance, even if they show
promise in terms of their potency, selectivity and efficacy.
But, liabilities that make compounds unsuitable for IR
oral delivery may be overcome by CR oral delivery.
These liabilities include poor solubility, low permeability
and extensive metabolism in the upper GI tract, short
plasma half-life, and a narrow therapeutic index. If
recognized and evaluated during lead optimization, CR
drug delivery could enable successful advancement of
such compounds.
Optimization of a lead series for CR delivery requires
an assessment of how solubility, dissolution, absorption
and metabolism affect the pharmacokinetic (PK) profile
of the compound. Here, we apply computational
modeling to evaluate the impact of CR drug delivery on
the PK profile using in vitro and in vivo pre-clinical
measurements as inputs.
Experimental and Computational Methods
Absorption of a compound in the lower as well as the
upper GI tract is a key requirement for applying oral CR
drug delivery to sustain circulating plasma concentrations.
To evaluate the feasibility of applying controlled release
oral delivery to extend the duration of action of the -
carbolines, we applied the following strategy.
From a series of -carboline analogues, we selected
three lead compounds (A, B and C) and measured their
passive permeability in a parallel artificial membrane
permeability assay (PAMPA). Next, we measured their
solubilities versus pH to ensure that solubility would not
limit their absorption in vivo. We then performed intra-
duodenal and intra-colonic dosing studies in a
catheterized rat model for the three compounds and
risperidone to assess the relative upper and lower GI
absorption of each compound. Lastly, for the compound
(B) with the highest colonic absorption in the rat model
and for risperidone, we conducted site-specific dosing
studies in a catheterized dog model. Our goal was to
identify at least one member of the series with the
potential to achieve QD dosing through CR oral delivery.
Risperidone was used as a positive comparator because it
has substantial human colonic absorption and is related
structurally to the carbolines.
Our principal computational tools were GastroPlusTM
and its supporting program QMPRPlusTM
(SimulationsPlus, Inc., Lancaster, CA). GastroPlus
implements an advanced compartmental absorption and
transit (ACAT) model of the GI tract (Agoram et al.,
2001), based on the original model of Yu and Amidon
(1996, 1999), that couples to compartmental PK models
via rate equations governing the release, dissolution,
transit, absorption, distribution, metabolism and
elimination of a compound. The outputs of the model are
bioavailability, and liver and plasma concentrations as
functions of time.
To predict plasma profiles, values for the molecular
weight, Log P, pKas, solubility vs pH, aqueous diffusion
coefficient, and GI permeability must be provided. With
the exception of solubility as a function of pH, we
utilized QMPRPlus and ACD pKa DB (ACD Labs,
Toronto, Canada) to estimate these values in silico. In
addition, a pharmacokinetic model must be specified:
minimally, a clearance and volume of distribution. PK
analyses of the iv bolus data were conducted via the
PKPlus module within GastroPlus. Oral bioavailability
(BA) was calculated by comparing dose-normalized area
under the curves (AUCs) following site-specific and iv
bolus dosing.
Results and Discussion
The plasma concentration profiles for compound B
observed after duodenal and colonic dosing in rats are
shown in Figure 1. Absorption is rapid in both cases, with
tmax reached within an hour. The profiles are almost
identical, with a colonic-duodenal relative BA of 91%
(absolute BAs are 81% and 74%, respectively). The
predicted plasma profiles match the observed data well
between one and four hours. The predicted rate of
absorption may exceed the observed rate, but there are
2. insufficient data at early times to resolve this point.
Beyond four hours, the simulation predicts a slightly more
rapid decline than observed. On the whole, however, the
results of the simulation are quite good, with root mean
square (RMS) relative errors of 0.25 and 0.20,
respectively.
Fig. 1 Observed and predicted plasma concentrations (±
SEM, N=4) following site-specific dosing of compound B
in rats (0.1 mg/kg)
The plasma profiles observed after duodenal and
colonic dosing in dogs are shown in Figure 2. Absorption
is rapid, and the terminal phase is more rapid than in the
mouse. The profiles are quite similar, except at 0.25 hrs,
at which time there is large variability in the duodenal
data, which may be inaccurate. The similarity of the
profiles at all other times suggests so. The simulation of
duodenal dosing predicts the amplitudes well, but the
absorption rate appears to be too low, which shifts the
profile to later times. The predicted colonic profile
captures the absorption phase but the clearance appears to
be somewhat too large. The RMS relative errors are 0.34
and 0.47, respectively.
Fig. 2 Observed and predicted plasma concentrations (±
SEM, N=4) following site-specific dosing of compound B
in dogs (1.8 mg/kg)
Predictions for the CR delivery of compound B are
shown in Figure 3, along with a minimum effective
plasma concentration (dotted line) for D2 antagonism,
derived from studies on protection of dogs from
apomorphine-induced emesis. The release profile, shown
inset, is typical of an OROSTM
push-pull design, scaled to
match the transit time of the dog GI tract. Our
calculations suggest that CR delivery can achieve quasi-
steady plasma concentrations greater than the threshold
for efficacy for longer durations than IR delivery. CR
delivery may accomplish this at slightly lower doses than
IR delivery, although more time is required to reach
effective plasma levels initially.
Fig. 3 Predicted plasma concentrations following CR oral
delivery of compound B. The dotted line indicates a
minimum effective plasma concentration (5 ng/ml). The
release profile is inset.
Conclusions
We have used a combination of in vitro and in vivo
data and in silico estimates to simulate numerically the IR
and CR oral delivery of three -carboline analogues of
risperidone. We are able to reproduce the observed
plasma profiles of the compounds following duodenal and
colonic site-specific dosing in the rat and dog, and predict
the plasma profiles that would be observed in the dog
following CR delivery. These latter predictions, when
combined with observations from a model for efficacy,
suggest that CR delivery achieves quasi-steady plasma
concentrations and extended duration of action relative to
IR delivery.
Pending the availability of human PK data through
allometric scaling or studies in vivo, these kinds of
calculations can be extended to aid in the assessment of
lead series of compounds in the latter stages of drug
discovery.
References
(1) Agoram, B, Woltosz, WS and Bolger, MB. Adv. Drug
Delivery Rev. 50, S41-S67 (2001).
(2) Yu, LX, Crison, JR and Amidon, GL. Int. J. Pharm.
140, 111-118 (1996).
(3) Yu, LX and Amidon, GL. Int. J. Pharm. 186, 119-125
(1999).
JNJ-16558711
0
1
2
3
4
5
6
0 2 4 6 8
Time (hours)
PlasmaConc.
(ng/ml)
Duod Obs
Colon Obs
Duod Pred
Colon Pred
JNJ-16558711
0
1
2
3
4
5
6
0 2 4 6 8
Time (hours)
PlasmaConc.
(ng/ml)
Duod Obs
Colon Obs
Duod Pred
Colon Pred
0
16
32
48
64
80
0 2 4 6 8 10 12 14 16
Time (hours)
PlasmaConc.(ng/ml)
Duod Obs
Colon Obs
OROS 1 mg/kg
OROS 3 mg/kg
Min Effective Cp0
20
40
60
80
100
0 2 4 6 8 10
Time (hrs)
%Released
0
28
56
84
0 2 4 6 8
Time (hours)
PlasmaConc.
(ng/ml)
Duod Obs
Colon Obs
Duod Pred
Colon Pred