Active Transport Processes Research Articles

Exploring Kp,uu,BBB values smaller than unity in remoxipride: A physiologically-based CNS model approach highlighting brain metabolism in drugs with passive blood-brain barrier transport

(Aim)Kp,uu,BBB values are crucial indicators of drug distribution into the brain, representing the steady-state relationship between unbound concentrations in plasma and in brain extracellular fluid (brainECF). Kp,uu,BBB values < 1 are often interpreted as indicators of dominant active efflux transport processes at the blood-brain barrier (BBB). However, the potential impact of brain metabolism on this value is typically not addressed. In this study, we investigated the brain distribution of remoxipride, as a paradigm compound for passive BBB transport with yet unexplained brain elimination that was hypothesized to represent brain metabolism. (Methods)The physiologically-based LeiCNS pharmacokinetic predictor (LeiCNS-PK model) was used to compare brain distribution of remoxipride with and without Michaelis-Menten kinetics at the BBB and/or brain cell organelle levels. To that end, multiple in-house (IV 0.7, 3.5, 4, 5.2, 7, 8, 14 and 16 mg kg-1) and external (IV 4 and 8 mg kg-1) rat microdialysis studies plasma and brainECF data were analysed. (Results)The incorporation of active elimination through presumed brain metabolism of remoxipride in the LeiCNS-PK model significantly improved the prediction accuracy of experimentally observed brainECF profiles of this drug. The model integrated with brain metabolism in both barriers and organelles levels is named LeiCNS-PK3.5. (Conclusion)For drugs with Kp,uu,BBB values < 1, not only the current interpretation of dominant BBB efflux transport, but also potential brain metabolism needs to be considered, especially because these may be concentration dependent. This will improve the mechanistic understanding of the processes that determine brain PK profiles.

Stability and deformation of biomolecular condensates under the action of shear flow.

Biomolecular condensates play a key role in cytoplasmic compartmentalization and cell functioning. Despite extensive research on the physico-chemical, thermodynamic, or crowding aspects of the formation and stabilization of the condensates, one less studied feature is the role of external perturbative fluid flow. In fact, in living cells, shear stress may arise from streaming or active transport processes. Here, we investigate how biomolecular condensates are deformed under different types of shear flows. We first model Couette flow perturbations via two-way coupling between the condensate dynamics and fluid flow by deploying Lattice Boltzmann Molecular Dynamics. We then show that a simplified approach where the shear flow acts as a static perturbation (one-way coupling) reproduces the main features of the condensate deformation and dynamics as a function of the shear rate. With this approach, which can be easily implemented in molecular dynamics simulations, we analyze the behavior of biomolecular condensates described through residue-based coarse-grained models, including intrinsically disordered proteins and protein/RNA mixtures. At lower shear rates, the fluid triggers the deformation of the condensate (spherical to oblated object), while at higher shear rates, it becomes extremely deformed (oblated or elongated object). At very high shear rates, the condensates are fragmented. We also compare how condensates of different sizes and composition respond to shear perturbation, and how their internal structure is altered by external flow. Finally, we consider the Poiseuille flow that realistically models the behavior in microfluidic devices in order to suggest potential experimental designs for investigating fluid perturbations in vitro.

Vesicle and reaction-diffusion hybrid modeling with STEPS

Vesicles carry out many essential functions within cells through the processes of endocytosis, exocytosis, and passive and active transport. This includes transporting and delivering molecules between different parts of the cell, and storing and releasing neurotransmitters in neurons. To date, computational simulation of these key biological players has been rather limited and has not advanced at the same pace as other aspects of cell modeling, restricting the realism of computational models. We describe a general vesicle modeling tool that has been designed for wide application to a variety of cell models, implemented within our software STochastic Engine for Pathway Simulation (STEPS), a stochastic reaction-diffusion simulator that supports realistic reconstructions of cell tissue in tetrahedral meshes. The implementation is validated in an extensive test suite, parallel performance is demonstrated in a realistic synaptic bouton model, and example models are visualized in a Blender extension module.

Unveiling the variability in cadmium accumulation and tolerance characteristics: a comparative study of Basma and Yunyan 87 tobacco varieties

ABSTRACT Tobacco (Nicotiana tabacum L.) shows promise for remediating Cd-contaminated soil due to its significant Cd accumulation capabilities. Although various tobacco varieties exhibit distinct Cd bioaccumulation capacities, a comprehensive understanding of the underlying mechanisms is lacking. This study, conducted using hydroponics, explores differences in Cd accumulation and tolerance mechanisms between two tobacco varieties, Basma and Yunyan 87. The results showed that Cd stress reduced the dry weight, tolerance index, and root morphology for both varieties. Basma exhibited a relatively smaller decline in these indices compared to Yunyan 87. Moreover, Basma demonstrated a higher Cd bioconcentration factor (BCF), concentration, and accumulated content, signifying its superior tolerance and bioaccumulation capacity to Cd compared to Yunyan 87. The Carbonyl Cyanide3-ChloroPhenylhydrazone (CCCP) addition resulted in reduced Cd accumulation and BCFs in both tobacco species. This effect was more pronounced in Basma, suggesting that Basma relies more on an active transport process than Yunyan 87. This could potentially explain its enhanced bioaccumulation ability. Subcellular Cd distribution analysis revealed Basma's preference for distributing Cd in soluble fractions, while Yunyan 87 favoured the cell wall fractions. Transmission electron microscope showed that Basma's organelles were less damaged than Yunyan 87's under Cd stress, possibly contributing to the superior tolerance of Basma. Therefore, these results provided a theoretical foundation for development of Cd-contaminated soil tobacco remediation technology.

Гомеостаз концентрацій кальцію, калію, натрію сперми бугаїв і матково-вагінального слизу корів

The difference in concentration indicators (mM) of alkali metal ions (Са2+, К+, Na+) and the calculated ratio indices (RI:1) of their pairs (Nа+:Са2+, К+:Са2+, Nа+:К+) in bull semen samples and uterine-vaginal mucus (UVM) of the Ukrainian black-spotted breed cows was determined and suggests that the ability of sperm to passively and/or actively move through the channels and ducts of the genital organs can be associated with the physicochemical processes of passive diffusion and active transport of substances that occur in the "sperm – UVM " system. The power of the energy of chemical and electrochemical concentration gradients and the power of ion pumps of the osmotic pressure of inorganic and oncotic – organic substances promotes the movement of spermatozoa to the place of their contact with the egg cell. In favor of the proposed hypothesis indicate the obtained probable (Р ˂ 0.001) results of the stoichiometry parameters of the concentrations of Ca2+ (10 vs. 6) and Na+ (62 vs. 1066 mM) of sperm and UVM, respectively. The determined difference is also illustrated by the unequal indices of ion pair concentration ratios. If their value in sperm samples is directed from the pair Na+:К+ to the pair Na+:Са2+ (1.4:1 → 5:1 →6:1), then in the samples of UVM – from К+:Са2+ to Na+: Ca2+ (8:1 → 23:1 → 193:1). The difference in indices of a number of pairs (К+:Са2+ → Nа+:К+ → Nа+:Са2+) of sperm and UVM is directed from a smaller to a larger value (3:1 ˂ 22:1 ˂ 187:1). If the calculated changes are expressed as percentages, then the difference in indicators in the samples of the UVM, respectively, is 41; 94 and 97 %, which is in 2; 16 and 30 times more than sperm samples. This may mean that the determined significant difference in the physical and chemical state of organic and inorganic substances in the environment of the channels and ducts of the genital organs of cows creates conditions that contribute to the active and passive movement of sperm through the channels and ducts of their genital organs

Study transport of hesperidin based on the DPPC lipid model and the BSA transport model

Hesperidin (HE), a significant flavonoid polyphenolic compound present in citrus plants, exhibits diverse pharmacological effects. Considering the crucial involvement of biological membranes and transporter proteins in the transportation and biological processes of HE, it becomes essential to comprehend the potential mechanisms through which HE interacts with membranes and transporter proteins. In order to simulate the process of active molecule transport, a cell membrane model consisting of 1,2-dipalmitoyl-n-glycero-3-phosphatidylcholine (DPPC) and a transporter protein model of bovine serum albumin (BSA) were employed for investigation. The present study aimed to investigate the mechanism of action of hesperidin (HE) in DPPC and BSA using fluorescence quenching, Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The localization and interaction of HE within liposomes were also elucidated. Furthermore, the binding of BSA and HE was analyzed through UV/Vis absorption spectroscopy, fluorescence spectroscopy, infrared spectroscopy, and computational biology techniques. Computational biology analysis revealed that the binding between HE and BSA primarily occurred via hydrogen bonding and hydrophobic interactions. This study aimed to investigate the role and mechanism of HE in the DPPC cell membrane model and the BSA transporter protein model, thereby offering novel insights into the action of HE in DPPC and BSA.

Membrane Transport, Molecular Machines, and Maxwell's Demon

AbstractThe spontaneous generation of transmembrane gradients is an important fundamental research goal for artificial nanotechnology. The active transport processes that give rise to such gradients directly mirror the famous Maxwell's Demon thought experiment, where a Demon partitions particles between two chambers to generate a nonequilibrium state. Despite these similarities, discussion of Maxwell's Demon is absent in the literature on artificial membrane transport. By contrast, the emergence of rational design principles for nonequilibrium artificial molecular motors can trace its intellectual roots directly to this famous thought experiment. This perspective highlights the links between Maxwell's Demon and nonequilibrium machines, and argues that understanding the implications of this 19th century thought experiment is crucial to the future development of transmembrane active transport processes.

Investigations Towards Tryptophan Uptake and Transport Across an In Vitro Model of the Oral Mucosa Epithelium.

Tryptophan is an essential amino acid and plays an important role in several metabolic processes relevant for the human health. As the main metabolic pathway for tryptophan along the kynurenine axis is involved in inflammatory responses, changed metabolite levels can be used to monitor inflammatory diseases such as ulcerative colitis. As a progenitor of serotonin, altered tryptophan levels have been related to several neurogenerative diseases as well as depression or anxiety. While tryptophan concentrations are commonly evaluated in serum, a non-invasive detection approach using saliva might offer significant advantages, especially during long-term treatments of patients or elderly. In order to estimate whether active transport processes for tryptophan might contribute to a potential correlation between blood and saliva tryptophan concentrations, we investigated tryptophan's transport across an established oral mucosa in vitro model. Interestingly, treatment with tryptophan revealed a concentration dependent secretion of tryptophan and the presence of a saturable transporter while transport studies with deuterated tryptophan displayed increased permeability from the saliva to the blood compartment. Protein analysis demonstrated a distinct expression of L-type amino acid transporter 1 (LAT1), the major transporter for tryptophan, and exposure to inhibitors (2 -amino-2-norbornanecarboxylic acid (BCH), L-leucine) led to increased tryptophan levels on the saliva side. Additionally, exposure to tryptophan in equilibrium studies resulted in a regulation of LAT1 at the mRNA level. The data collected in this study suggest the participation of active transport mechanisms for tryptophan across the oral mucosa epithelium. Future studies should investigate the transport of tryptophan across salivary gland epithelia in order to enable a comprehensive understanding of tryptophan exchange at the blood-saliva barrier.

Stability Issues in Electrochemical CO2 Reduction: Recent Advances in Fundamental Understanding and Design Strategies.

Electrochemical CO2 reduction reaction (CO2 RR) offers a promising approach to close the anthropogenic carbon cycle and store intermittent renewable energy in fuels or chemicals. On the path to commercializing this technology, achieving the long-term operation stability is a central requirement but still confronts challenges. This motivates to organize the present review to systematically discuss the stability issue of CO2 RR. This review starts from the fundamental understanding on the destabilization mechanisms of CO2 RR, with focus on the degradation of electrocatalyst and change of reaction microenvironment during continuous electrolysis. Subsequently, recent efforts on catalyst design to stabilize the active sites are summarized, where increasing atomic binding strength to resist surface reconstruction is highlighted. Next, the optimization of electrolysis system to enhance the operation stability by maintaining reaction microenvironment especially mitigating flooding and carbonate problems is demonstrated. The manipulation on operation conditions also enables to prolong CO2 RR lifespan through recovering catalytically active sites and mass transport process. This review finally ends up by indicating the challenges and future opportunities.

Interaction and mechanism between arginine functionalized hydroxyapatite nanoparticles and human umbilical vein endothelial cells

The interaction between terbium-doped arginine functionalized hydroxyapatite nanoparticles (Arg@HAPTb NPs) and cells, and the hindered endocytosis mechanisms of human umbilical vein endothelial cells (HUVECs) were studied by observing the cell uptake of Arg@HAPTb NPs with laser scanning confocal microscopy. Average fluorescence intensity of cells after uptaking different concentrations of NPs was determined by flow cytometer. The results indicate that internalized Arg@HAPTb NPs mainly exist in the cytoplasm of HUVECs, and most of them distribute around the cell nuclei. The entrapment of Arg@HAPTb NPs shows time-dependent and concentration- dependent manners with optimal time of 4 h and concentration of 50 mg/L. Arginine modification significantly improves the uptake efficiency of HAPTb NPs. The entry of Arg@HAPTb NPs into HUVECs is mainly through concave protein-mediated endocytosis, an energy-dependent active transport process.

Alkaloids in commercial preparations of California poppy – Quantification, intestinal permeability and microbiota interactions

California poppy products are commonly used for the treatment of nervousness, anxiety and sleeping disorders. Pharmacologically relevant constituents include the main alkaloids californidine, escholtzine and protopine. However, only limited information is available about the alkaloid content in commercial preparations and their intestinal absorption. Moreover, a possible metabolization of these alkaloids by the gut microbiota, and their impact on microbial activity and viability have not been investigated. Californidine, escholtzine and protopine were quantified by UHPLC-MS/MS in eight commercial California poppy products. The intestinal permeability of alkaloids was studied in Caco-2 cell as a model for absorption in the small intestine. The gut microbial biotransformation was explored in artificial gut microbiota from the in vitro PolyFermS model. In addition, the impact of these alkaloids and a California poppy extract on the microbial production of short-chain fatty acids (SCFAs) and the viability of microbiota was investigated. Contents of californidine, escholtzine and protopine in California poppy products were in the ranges of 0.13–2.55, 0.05–0.63 and 0.008–0.200 mg/g, respectively. In the Caco-2 cell model, californidine was low-to-moderately permeable while escholtzine and protopine were highly permeable. An active transport process was potentially involved in the transfer of the three alkaloids. The three compounds were not metabolized by the artificial gut microbiota over 24 h. Neither the California poppy extract nor the alkaloids markedly impacted microbial SCFA production and bacterial viability.

Maize Grain Germination Is Accompanied by Acidification of the Environment

Seed germination is a complex process involving several stages, starting with the imbibition of water and ending with the emergence of the radicle. In the current study, we address the observation of an unexpected pH shift during the imbibition of maize grains. We used direct pH measurements of soak water, the pH indicator methyl red, and anatomical analysis to shed light on the acidification associated with maize (Zea mays L.) germination, a largely overlooked phenomenon. Our work shows that acidification during imbibition of maize grains is a two-step process: (i) early, rapid acidification (pH values up to 4.4), in which protons stored in the (dead) pericarp/testa are mobilised and rapidly diffuse into the surrounding medium, and (ii) late, delayed acidification (pH values just below 6), starting hours after contact of grains with water, representing an active transport process caused by living cells of the seed. We discuss the physiological mechanisms and ecological relevance of environmental acidification during maize grain germination.

Effect of aligned porous electrode thickness and pore size on bubble removal capability and hydrogen evolution reaction performance

Aligned porous electrodes with different pore sizes and thicknesses are prepared by freezing casting method, and the effect of the electrode thickness and pore size on hydrogen evolution reaction (HER) performance and bubble removal capability are experimentally studied. The results show that the pore size and thickness of the aligned porous electrodes have a significant impact on the HER performance by affecting the electrochemical active surface area (ECSA) and bubble transport process. The influence of pore sizes and electrode thicknesses on HER performance are different with current density. In the region of low current density, the effect of electrode thickness on electrochemical performance is more significant than that of pore size. While at high current density pore size becomes a limiting factor for electrochemical performance. Additionally, the Δζγ is proposed to evaluate the bubble removal capability, and a small Δζγ indicates the good bubble removal efficiency.

Intestinal permeability and gut microbiota interactions of pharmacologically active compounds in valerian and St. John’s wort

Phytomedicines such as valerian and St. John’s wort are widely used for the treatment of sleeping disorders, anxiety and mild depression. They are perceived as safe alternatives to synthetic drugs, but limited information is available on the intestinal absorption and interaction with human intestinal microbiota of pharmacologically relevant constituents valerenic acid in valerian, and hyperforin and hypericin in St. John’s wort. The intestinal permeability of these compounds and the antidepressant and anxiolytic drugs citalopram and diazepam was investigated in the Caco-2 cell model with bidirectional transport experiments. In addition, interaction of compounds and herbal extracts with intestinal microbiota was evaluated in artificial human gut microbiota. Microbiota-mediated metabolisation of compounds was assessed, and bacterial viability and short-chain fatty acids (SCFA) production were measured in the presence of compounds or herbal extracts. Valerenic acid and hyperforin were highly permeable in Caco-2 cell monolayers. Hypericin showed low-to-moderate permeability. An active transport process was potentially involved in the transfer of valerenic acid. Hyperforin and hypericin were mainly transported through passive transcellular diffusion. All compounds were not metabolized over 24 h in the artificial gut microbiota. Microbial SCFA production and bacterial viability was not substantially impaired nor promoted by exposure to the compounds or herbal extracts.

The Mobility of Neurofilaments in Mature Myelinated Axons of Adult Mice.

Studies in cultured neurons have shown that neurofilaments are cargoes of axonal transport that move rapidly but intermittently along microtubule tracks. However, the extent to which axonal neurofilaments move in vivo has been controversial. Some researchers have proposed that most axonally transported neurofilaments are deposited into a persistently stationary network and that only a small proportion of axonal neurofilaments are transported in mature axons. Here we use the fluorescence photoactivation pulse-escape technique to test this hypothesis in intact peripheral nerves of adult male hThy1-paGFP-NFM mice, which express low levels of mouse neurofilament protein M tagged with photoactivatable GFP. Neurofilaments were photoactivated in short segments of large, myelinated axons, and the mobility of these fluorescently tagged polymers was determined by analyzing the kinetics of their departure. Our results show that >80% of the fluorescence departed the window within 3 h after activation, indicating a highly mobile neurofilament population. The movement was blocked by glycolytic inhibitors, confirming that it was an active transport process. Thus, we find no evidence for a substantial stationary neurofilament population. By extrapolation of the decay kinetics, we predict that 99% of the neurofilaments would have exited the activation window after 10 h. These data support a dynamic view of the neuronal cytoskeleton in which neurofilaments cycle repeatedly between moving and pausing states throughout their journey along the axon, even in mature myelinated axons. The filaments spend a large proportion of their time pausing, but on a timescale of hours, most of them move.

Thermodynamically consistent stochastic models for active transmembrane transport processes.

Simulating the full transport cycle of an active transporter driven an ionic electrochemical transmembrane gradient with atomistic detail has been challenging because full cycle completions occur on typical time scales ranging from milliseconds to seconds, out of reach of typical molecular dynamic (MD) simulations. Instead, multiscaling approaches have been developed that break the cycle into elementary steps for which kinetic and equilibrium parameters can be obtained from MD. These parameters are combined in a stochastic kinetic model whose master equation is solved under varying external conditions such as ion concentrations and membrane potential. We developed two improvements for this well-known approach: (1) We introduce the multibind algorithm to derive thermodynamically consistent state free energies and rates from input free energy differences and rates; without such a step, a kinetic model is not guaranteed to obey the laws of thermodynamics and may produce nonsensical results. We also show how the resulting model can be used for parameter inference of microscopic parameters from macroscopic experimental measurements. (2) As an alternative to the numerical solution of the steady state problem, one can exactly solve it using Hill's diagrammatic approach. Our Kinetic Diagram Analysis (KDA) implementation of Hill's method yields symbolic rational expressions for arbitrary kinetic graphs that can be analytically manipulated and directly evaluated. We demonstrate the kinetic graph multiscale approach for sodium/proton antiporters.

A Quantum Mechanics-Based Method to Predict Intramolecular Hydrogen Bond Formation Reflecting P-glycoprotein Recognition.

Passive membrane permeability and an active transport process are key determinants for penetrating the blood-brain barrier. P-glycoprotein (P-gp), a well-known transporter, serves as the primary gatekeeper, having broad substrate specificity. A strategy to increase passive permeability and impair P-gp recognition is intramolecular hydrogen bonding (IMHB). 3 is a potent brain penetrant BACE1 inhibitor with high permeability and low P-gp recognition, although slight modifications to its tail amide group significantly affect P-gp efflux. We hypothesized that the difference in the propensity to form IMHB could impact P-gp recognition. Single-bond rotation at the tail group enables both IMHB forming and unforming conformations. We developed a quantum-mechanics-based method to predict IMHB formation ratios (IMHBRs). In a given data set, IMHBRs accounted for the corresponding temperature coefficients measured in NMR experiments, correlating with P-gp efflux ratios. Furthermore, the method was applied in hNK2 receptor antagonists, demonstrating that the IMHBR could be applied to other drug targets involving IMHB.

Testing the ion-current model for flagellar length sensing and IFT regulation.

Eukaryotic cilia and flagella are microtubule-based organelles whose relatively simple shape makes them ideal for investigating the fundamental question of organelle size regulation. Most of the flagellar materials are transported from the cell body via an active transport process called intraflagellar transport (IFT). The rate of IFT entry into flagella, known as IFT injection, has been shown to negatively correlate with flagellar length. However, it remains unknown how the cell measures the length of its flagella and controls IFT injection. One of the most-discussed theoretical models for length sensing to control IFT is the ion-current model, which posits that there is a uniform distribution of Ca2+ channels along the flagellum and that the Ca2+ current from the flagellum into the cell body increases linearly with flagellar length. In this model, the cell uses the Ca2+ current to negatively regulate IFT injection. The recent discovery that IFT entry into flagella is regulated by the phosphorylation of kinesin through a calcium-dependent protein kinase has provided further impetus for the ion-current model. To test this model, we measured and manipulated the levels of Ca2+ inside of Chlamydomonas flagella and quantified IFT injection. Although the concentration of Ca2+ inside of flagella was weakly correlated with the length of flagella, we found that IFT injection was reduced in calcium-deficient flagella, rather than increased as the model predicted, and that variation in IFT injection was uncorrelated with the occurrence of flagellar Ca2+ spikes. Thus, Ca2+ does not appear to function as a negative regulator of IFT injection, hence it cannot form the basis of a stable length control system.

Real Time In Vivo Evaluation of Mitochondrial Activity and Brain Functions during Ischemic Stroke

More than 50% of total energy consumed by the brain is utilized by active transport processes which are responsible for keeping the ionic homeostasis in the brain. Under an ischemic condition, energy availability is limited, and, as a result, inhibition of the ion pumps is unavoidable. The initial consequence of such inhibition is a gradual accumulation of K+ in the extracellular space leading to a second phase of the ischemic depolarization phenomenon. During ischemic depolarization, extracellular K+ will increase 15-20-fold, while extracellular Ca2+ is decreasing 10 fold. Another optional effect of mild ischemia is the development of Cortical Spreading Depression due to the leakage of K+ into the extracellular space. The Mongolian gerbil provides a very useful animal model to study the effects of ischemia on brain functions. The aims of the study were as follows: (1) To elucidate the mechanism behind the development of ischemic depolarization or cortical spreading depression under unilateral and bilateral carotid artery occlusion. (2) To correlate the kinetics of the recovery processes to the level of ischemia. We tested the correlation between energy depletion level (evaluated by intramitochondrial NADH redox state and Cerebral Blood Flow) and the development of ischemic depolarization or cortical spreading depression (evaluated by extracellular K+, H+, Ca2+, DC potential and 366 nm reflectance changes) under partial and complete ischemia using the multiparametric monitoring system. The results could be summarized as follows: (1) Under bilateral occlusion, in all gerbils the ischemic depolarization was recorded within 1-2 min. (2) Under unilateral occlusion, the level of ischemia obtained was significantly smaller and led to the ischemic depolarization in about 60% of the gerbils. (3) The K+ leakage during the ischemic depolarization had an 'all or none' nature in terms of maximal K÷ levels and time to reach it. (4) The main effect of various lengths of bilateral occlusion was on the recovery time of extracellular K+ level. (5) Cortical spreading depression develop in most cases during the recovery from the ischemic event when ischemic depolarization was not recorded under the ischemic episode.

The Use of Pregnancy Physiologically Based Pharmacokinetic Modeling for Renally Cleared Drugs.

Physiologically based pharmacokinetic modeling (PBPK) could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations where there are currently no available clinical data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by the kidney. Models were evaluated for ceftazidime, cefuroxime, metformin, oseltamivir, and amoxicillin. Because the passive renal process contributes significantly to the renal elimination of these drugs and changes of the process during pregnancy have been implemented in existing pregnancy physiology models, simulations using these models can reasonably describe the pharmacokinetics of ceftazidime changes during pregnancy and appears to generally capture the changes in the other medicines; however, there are insufficient data on drugs solely passively cleared to fully qualify the models. In addition, in many cases, active transport processes are involved in a drug's renal clearance. Knowledge of changes in renal transport functions during pregnancy is emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is a work in progress. Filling this gap is expected to further enhance predictive performance of the models and increase the confidence in predicting pharmacokinetic changes in pregnant women for other renally cleared drugs.