Functional and Pharmacological Comparison of Human and Mouse Na+/Taurocholate Cotransporting Polypeptide (NTCP)

2021 ◽  
pp. 247255522110175
Author(s):  
Saskia Floerl ◽  
Annett Kuehne ◽  
Joachim Geyer ◽  
Juergen Brockmoeller ◽  
Mladen V. Tzvetkov ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Drug Transport ◽  
Species Differences ◽  
Basolateral Membrane ◽  
Pharmacokinetic Data ◽  
Hepatic Transport ◽  
Inhibitory Potency ◽  
The Difference ◽  
Inhibition Pattern ◽  
Human And Mouse

The Na+/taurocholate cotransporting polypeptide (NTCP) is located in the basolateral membrane of hepatocytes, where it transports bile acids from the portal blood back into hepatocytes. Furthermore, NTCP has a role for the hepatic transport of some drugs. Extrapolation of drug transport data from rodents to humans is not always possible, because species differences in the expression level, localization, affinity, and substrate selectivity of relevant transport proteins must be considered. In the present study, a functional comparison of human NTCP (hNTCP) and mouse Ntcp (mNtcp) showed similar Km values of 67 ± 10 µM and 104 ± 9 µM for the probe substrate estrone-3-sulfate as well as of 258 ± 42 µM and 199 ± 13 µM for the drug rosuvastatin, respectively. IC50 values for the probe inhibitor cyclosporine A were 3.1 ± 0.3 µM for hNTCP and 1.6 ± 0.4 µM for mNtcp. In a drug and pesticide inhibitory screening on both transporters, 4 of the 15 tested drugs (cyclosporine A, benzbromarone, MK571, and fluvastatin) showed high inhibitory potency, but only slight inhibition was observed for the 13 tested pesticides. Among these compounds, only four drugs and three pesticides showed significant differences in their inhibition pattern on hNTCP and mNtcp. Most pronounced was the difference for benzbromarone with a fivefold higher IC50 for mNtcp (27 ± 10 µM) than for hNTCP (5.5 ± 0.6 µM). In conclusion, we found a strong correlation between the transport kinetics and inhibition pattern among hNTCP and mNtcp. However, specific compounds, such as benzbromarone, showed clear species differences. Such species differences have to be considered when pharmacokinetic data are transferred from rodent to humans.

scholarly journals A “Smart” Biosensor-Enabled Intravascular Catheter and Platform for Dynamic Delivery of Propofol to “Close the Loop” for Total Intravenous Anesthesia

2021 ◽  
Vol 186 (Supplement_1) ◽  
pp. 370-377
Author(s):  
Edward Chaum ◽  
Ernő Lindner
Keyword(s):  
Real Time ◽  
Drug Distribution ◽  
Population Based ◽  
Pharmacokinetic Data ◽  
Drug Infusion ◽  
Blood Concentrations ◽  
The Usa ◽  
The Difference ◽  
Automated Delivery

ABSTRACT Background Target-controlled infusion anesthesia is used worldwide to provide user-defined, stable, blood concentrations of propofol for sedation and anesthesia. The drug infusion is controlled by a microprocessor that uses population-based pharmacokinetic data and patient biometrics to estimate the required infusion rate to replace losses from the blood compartment due to drug distribution and metabolism. The objective of the research was to develop and validate a method to detect and quantify propofol levels in the blood, to improve the safety of propofol use, and to demonstrate a pathway for regulatory approval for its use in the USA. Methods We conceptualized and prototyped a novel “smart” biosensor-enabled intravenous catheter capable of quantifying propofol at physiologic levels in the blood, in real time. The clinical embodiment of the platform is comprised of a “smart” biosensor-enabled catheter prototype, a signal generation/detection readout display, and a driving electronics software. The biosensor was validated in vitro using a variety of electrochemical methods in both static and flow systems with biofluids, including blood. Results We present data demonstrating the experimental detection and quantification of propofol at sub-micromolar concentrations using this biosensor and method. Detection of the drug is rapid and stable with negligible biofouling due to the sensor coating. It shows a linear correlation with mass spectroscopy methods. An intuitive graphical user interface was developed to: (1) detect and quantify the propofol sensor signal, (2) determine the difference between targeted and actual propofol concentration, (3) communicate the variance in real time, and (4) use the output of the controller to drive drug delivery from an in-line syringe pump. The automated delivery and maintenance of propofol levels was demonstrated in a modeled benchtop “patient” applying the known pharmacokinetics of the drug using published algorithms. Conclusions We present a proof-of-concept and in vitro validation of accurate electrochemical quantification of propofol directly from the blood and the design and prototyping of a “smart,” indwelling, biosensor-enabled catheter and demonstrate feedback hardware and software architecture permitting accurate measurement of propofol in blood in real time. The controller platform is shown to permit autonomous, “closed-loop” delivery of the drug and maintenance of user-defined propofol levels in a dynamic flow model.

scholarly journals Putative linear motifs mediate the trafficking to apical and basolateral membranes

2020 ◽  
Author(s):  
Laszlo Dobson ◽  
András Zeke ◽  
Levente Szekeres ◽  
Tamás Langó ◽  
Gábor Tusnády
Keyword(s):  
Epithelial Cells ◽  
Drug Transport ◽  
Basolateral Membrane ◽  
Transmembrane Proteins ◽  
Transport Processes ◽  
Membrane Domains ◽  
Protein Distribution ◽  
Basolateral Membranes ◽  
Linear Motifs ◽  
Cellular Components

AbstractCell polarity refers to the asymmetric organisation of cellular components in various cells. Epithelial cells are the best known examples of polarized cells, featuring apical and basolateral membrane domains. Despite huge efforts, the exact rules governing the protein distribution in such domains are still elusive. In this study we examined linear motifs accumulating in these parts and based on the results we prepared ‘Classical’ and Convolutional Neural Networks to classify human transmembrane proteins localizing into apical/basolateral membranes. Asymmetric expression of drug transporters results in vectorial drug transport, governing the pharmacokinetics of numerous substances, yet the data on how proteins are sorted in epithelial cells is very scattered. The provided dataset may offer help to experimentalists to characterize novel molecular targets to regulate transport processes more precisely.

Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells

1999 ◽  
Vol 277 (1) ◽  
pp. F84-F96 ◽  
Author(s):  
Shinya Ito ◽  
Cindy Woodland ◽  
Balázs Sarkadi ◽  
Guido Hockmann ◽  
Scott E. Walker ◽  
...  
Keyword(s):  
Drug Transport ◽  
Diffusion Processes ◽  
Efflux Pump ◽  
Mdck Cells ◽  
Basolateral Membrane ◽  
Drug Efflux ◽  
Drug Transfer ◽  
P Glycoprotein ◽  
Drug Efflux Pump ◽  
Apical Membranes

P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.

scholarly journals Indinavir Pharmacokinetics and Parmacodynamics in Children with Human Immunodeficiency Virus Infection

2000 ◽  
Vol 44 (3) ◽  
pp. 752-755 ◽  
Author(s):  
Giorgio Gatti ◽  
Alessandra Vigano' ◽  
Natascia Sala ◽  
Stefano Vella ◽  
Matteo Bassetti ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dosage Regimen ◽  
Renal Toxicity ◽  
Significant Negative Correlation ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Time Curve ◽  
Number Of Patients ◽  
Immunodeficiency Virus ◽  
The Difference

ABSTRACT The indinavir dosage regimen currently used for human immunodeficiency virus (HIV)-infected children is not based on pharmacokinetic data obtained in the target patient population. The purpose of our study was to characterize indinavir pharmacokinetics and pharmacodynamics in HIV-infected children. Eleven children (age range, 9.0 to 13.6 years; weight range, 21.7 to 56.0 kg) receiving indinavir (500 mg/m2 every 8 h) in combination with lamivudine and stavudine were studied. The correlation of indinavir pharmacokinetic parameters and demographic parameters was evaluated. Also, the pharmacodynamic relationship between parameters of indinavir exposure and parameters of renal toxicity and immunologic recovery was studied. The area under the indinavir concentration-time curve (AUC) and patient body surface area (BSA) showed a significant negative correlation (r = 0.73; P = 0.012). Patients with smaller BSA had excessive indinavir AUC compared to adults. On the other hand, the median minimum drug concentration in plasma (C min) was lower than that reported for adults. The maximum indinavir concentration in serum was higher in patients with renal toxicity (5 out of 11 children), but the difference was not statistically significant (15.3 ± 8.2 versus 9.8 ± 4.4 mg/liter; P = 0.19). There was a trend toward higher immunologic efficacy in patients with greater indinavir exposure: the time-averaged AUC of the percentage of CD4+ lymphocytes over the baseline value for patients with indinavir C min > 95% inhibitory concentration (IC95) was higher than in patients withC min < IC95(P = 0.068). Our study suggests that a dose reduction may be appropriate for children with small BSA and that a 6-h dosage regimen may be indicated for a substantial percentage of patients. Due to the low number of patients enrolled in this study, our results should be confirmed by a larger study.

Expression, regulation and function of intestinal drug transporters: an update

2017 ◽  
Vol 398 (2) ◽  
pp. 175-192 ◽  
Author(s):  
Janett Müller ◽  
Markus Keiser ◽  
Marek Drozdzik ◽  
Stefan Oswald
Keyword(s):  
Drug Absorption ◽  
Drug Transport ◽  
Drug Exposure ◽  
Oral Absorption ◽  
Basolateral Membrane ◽  
Oral Drug ◽  
Human Intestine ◽  
Intestinal Drug Absorption ◽  
Intestinal Transporters ◽  
And Function

Abstract Although oral drug administration is currently the favorable route of administration, intestinal drug absorption is challenged by several highly variable and poorly predictable processes such as gastrointestinal motility, intestinal drug solubility and intestinal metabolism. One further determinant identified and characterized during the last two decades is the intestinal drug transport that is mediated by several transmembrane proteins such as P-gp, BCRP, PEPT1 and OATP2B1. It is well-established that intestinal transporters can affect oral absorption of many drugs in a significant manner either by facilitating their cellular uptake or by pumping them back to gut lumen, which limits their oral bioavailability. Their functional relevance becomes even more apparent in cases of unwanted drug-drug interactions when concomitantly given drugs that cause transporter induction or inhibition, which in turn leads to increased or decreased drug exposure. The longitudinal expression of several intestinal transporters is not homogeneous along the human intestine, which may have functional implications on the preferable site of intestinal drug absorption. Besides the knowledge about the expression of pharmacologically relevant transporters in human intestinal tissue, their exact localization on the apical or basolateral membrane of enterocytes is also of interest but in several cases debatable. Finally, there is obviously a coordinative interplay of intestinal transporters (apical–basolateral), intestinal enzymes and transporters as well as intestinal and hepatic transporters. This review aims to give an updated overview about the expression, localization, regulation and function of clinically relevant transporter proteins in the human intestine.

Species Differences of Inhibitory Effects on P‐glycoprotein‐mediateD Drug Transport

2007 ◽  
Vol 96 (6) ◽  
pp. 1609-1618 ◽  
Author(s):  
Naoto Suzuyama ◽  
Miki Katoh ◽  
Toshiyuki Takeuchi ◽  
Sumie Yoshitomi ◽  
Tomoaki Higuchi ◽  
...  
Keyword(s):  
Drug Transport ◽  
Species Differences ◽  
Inhibitory Effects ◽  
P Glycoprotein

Chloride movement across basolateral membrane of Necturus gallbladder epithelium

1984 ◽  
Vol 247 (5) ◽  
pp. C495-C500 ◽  
Author(s):  
R. S. Fisher
Keyword(s):  
Basolateral Membrane ◽  
Membrane Voltage ◽  
Gallbladder Epithelium ◽  
Necturus Gallbladder ◽  
Concentration Changes ◽  
The Difference ◽  
K Concentration ◽  
Low Ionic Strength ◽  
Basolateral Membrane Potential

The relative Cl- and K+ sensitivity of the basolateral membrane potential of the in vitro Necturus gallbladder epithelium was determined. Tissues were punctured with two conventional glass microelectrodes to simultaneously measure the intracellular voltage (Vcs) and the voltage across the subepithelial connective tissue (Vse). Increasing the serosal K+ concentration from 2.5 to 25 mM caused a rapid monotonic depolarization of Vcs without changes of Vse. Reduction of serosal Cl- concentration (98 to 8 mM) caused a transient change of Vse. Thus the difference between Vcs and Vse more accurately reflected the basolateral membrane voltage (Vc) after Cl- concentration changes. The changes of Vc were small and biphasic in response to the decrease of serosal Cl- concentration. Perfusion of a low-ionic-strength solution in the mucosal chamber decreased the current that normally passes through the epithelium. Consistent with the notion that the basolateral voltage changes are attenuated by parallel pathways, the K+-induced depolarization increased by 80% under these conditions. The changes of Vc in response to Cl- substitutions were not different from those of tissue bathed in control solution. Thus the basolateral membrane voltage is relatively insensitive to changes of serosal Cl- concentration. I conclude that Cl- movement across the basolateral membrane is not attributable to simple electrodiffusion, and Cl- exit from these cells at this membrane must be electroneutral.

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