Physiologically-Based Modeling and Interspecies Prediction of Cisplatin Pharmacokinetics.

The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) modeling framework for cisplatin. The model was constructed based on 11 published data sets from rodents; and rabbit, dog, and human data were used to evaluate its utility in predicting plasma and tissue distribution of platinum in larger species, including humans. The model included biotransformation of cisplatin into mobile (k1) and fixed (k2) metabolites in all tissues, and subsequent conversion of fixed metabolites to mobile metabolites (k3) due to protein degradation and turnover. The model successfully captured complex pharmacokinetics of platinum in rodents, and all parameters were estimated with sufficient precision. A separate k2 parameter was estimated for each included tissue, and the relationship between the rates of formation of mobile and fixed metabolites was established through a scaling factor (k1=k2·SF, SF=0.74). For interspecies predictions, k1 and k2 were shared across all species, and k3 was scaled allometrically based on protein turnover rate (with an exponent of -0.28). Scaled PBPK model provided a good prediction of total platinum profiles in humans and reasonably captured platinum measurements in human tissues (as obtained from autopsy).

Using machine learning methods to analyze the association between urinary polycyclic aromatic hydrocarbons and chronic bowel disorders in American adults.

The etiology of chronic bowel disorders is multifaceted, with environmental exposure to harmful substances potentially playing a significant role in their pathogenesis. However, research on the correlation between polycyclic aromatic hydrocarbons (PAHs) and chronic bowel disorders remains limited. Using data from the National Health and Nutrition Examination Survey (NHANES) conducted in 2009-2010, we investigated the relationship between 9 PAHs and chronic diarrhea and constipation in U.S. adults. We employed unsupervised methods such as clustering and Principal Component Analysis (PCA) to identify participants with similar exposure patterns. Additionally, we used supervised learning techniques, namely weighted quantile sum (WQS) and Bayesian kernel machine (BKMR) regressions, to assess the association between PAHs and the occurrence of chronic diarrhea and chronic constipation. PCA identified three principal components in the unsupervised analysis, explaining 86.5% of the total PAH variability. The first component displayed a mild association with chronic diarrhea, but no correlation with chronic constipation. Participants were divided into three clusters via K-means clustering, based on PAH concentrations. Clusters with higher PAH exposure demonstrated an increased odds ratio for chronic diarrhea, but no meaningful connection with chronic constipation. In the supervised analysis, the WQS regression underscored a positive relationship between the PAH mixture and chronic diarrhea, with three PAHs significantly impacting the mixture effect. The mixture index showed no correlation with chronic constipation. BKMR analysis illustrated a positive trend in the impact of four specific PAHs on chronic diarrhea, given other metabolites were fixed at their 50th percentiles. Our results suggest a clear association between higher PAH exposure and an increased risk of chronic diarrhea, but not chronic constipation. It also underscores the potential role of specific PAHs in contributing to the risk of chronic diarrhea.

Nitrogen and phosphorus addition promote invasion success of invasive species via increased growth and nutrient accumulation under elevated CO2.

In the context of the resource allocation hypothesis regarding the trade-off between growth and defence, compared with native species, invasive species generally allocate more energy to growth and less energy to defence. However, it remains unclear how global change and nutrient enrichment will influence the competition between invasive species and co-occurring native species. Here, we tested whether nitrogen (N) and phosphorus (P) addition under elevated CO2 causes invasive species (Mikania micrantha and Chromolaena odorata) to produce greater biomass, higher growth-related compounds and lower defence-related compounds than native plants (Paederia scandens and Eupatorium chinense). We grew these native and invasive species with similar morphology with the addition of N and P under elevated CO2 in open-top chambers. The addition of N alone increased the relative growth rate (RGR) by 5.4% in invasive species, and its combination with P addition or elevated CO2 significantly increased the RGR of invasive species by 7.5 or 8.1%, respectively, and to a level higher than that of native species (by 14.4%, P < 0.01). Combined N + P addition under elevated CO2 decreased the amount of defence-related compounds in the leaf, including lipids (by 17.7%) and total structural carbohydrates (by 29.0%), whereas it increased the growth-related compounds in the leaf, including proteins (by 75.7%), minerals (by 9.6%) and total non-structural carbohydrates (by 8.5%). The increased concentrations of growth-related compounds were possibly associated with the increase in ribulose 1,5-bisphosphate carboxylase oxygenase content and mineral nutrition (magnesium, iron and calcium), all of which were higher in the invasive species than in the native species. These results suggest that rising atmospheric CO2 concentration and N deposition combined with nutrient enrichment will increase the growth of invasive species more than that of native species. Our result also suggests that invasive species respond more readily to produce growth-related compounds under an increased soil nutrient availability and elevated CO2.

Using three statistical methods to analyze the association between aldehyde exposure and markers of inflammation and oxidative stress.

BACKGROUND: Exposure to aldehydes has been linked to adverse health outcomes such as inflammation and oxidative stress, but research on the effects of these compounds is limited. This study is aimed at assessing the association between aldehyde exposure and markers of inflammation and oxidative stress. METHODS: The study used data from the NHANES 2013-2014 survey (n = 766) and employed multivariate linear models to investigate the relationship between aldehyde compounds and various markers of inflammation (alkaline phosphatase (ALP) level, absolute neutrophil count (ANC), and lymphocyte count) and oxidative stress (bilirubin, albumin, and iron levels) while controlling for other relevant factors. In addition to generalized linear regression, weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) analyses were applied to examine the single or overall effect of aldehyde compounds on the outcomes. RESULTS: In the multivariate linear regression model, each 1 standard deviation (SD) change in propanaldehyde and butyraldehyde was significantly associated with increases in serum iron levels (beta and 95% confidence interval, 3.25 (0.24, 6.27) and 8.40 (0.97, 15.83), respectively) and the lymphocyte count (0.10 (0.04, 0.16) and 0.18 (0.03, 0.34), respectively). In the WQS regression model, a significant association was discovered between the WQS index and both the albumin and iron levels. Furthermore, the results of the BKMR analysis showed that the overall impact of aldehyde compounds was significantly and positively correlated with the lymphocyte count, as well as the levels of albumin and iron, suggesting that these compounds may contribute to increased oxidative stress. CONCLUSIONS: This study reveals the close association between single or overall aldehyde compounds and markers of chronic inflammation and oxidative stress, which has essential guiding value for exploring the impact of environmental pollutants on population health.

A Retrospective Analysis of Preclinical and Clinical Pharmacokinetics from Administration of Long-Acting Aqueous Suspensions.

Administration of long-acting injectable suspensions is an increasingly common approach to increasing patient compliance and improving therapeutic efficacy through less frequent dosing. While several long-acting suspensions have recently been marketed, parameters modulating drug absorption from suspension-based formulations are not well understood. Further, methods for predicting clinical pharmacokinetic data from preclinical studies are not well established. Together, these limitations hamper compound selection, formulation design and formulation selection through heavy reliance on iterative optimization in preclinical and clinical studies. This article identifies key parameters influencing absorption from suspension-based formulations through compilation and analysis of preclinical and clinical pharmacokinetic data of seven compounds marketed as suspensions; achievable margins for predicting the clinical dose and input rate from preclinical studies as a function of the preclinical species, the clinical injection location and the intended therapeutic duration were also established.

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection.

BACKGROUND: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP). SETTING: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal. RESULTS: In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6  cells) were above the PK threshold for all dose levels. CONCLUSION: Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1.

Effects of elevated CO2 concentration and nitrogen addition on the chemical compositions, construction cost and payback time of subtropical trees in Cd-contaminated mesocosm soil.

Rising atmospheric CO2 concentration ([CO2]) and nitrogen (N) deposition are changing plant growth, physiological characteristics and chemical compositions; however, few studies have explored such impacts in a heavy metal-contaminated environment. In this study, we conducted an open-top chamber experiment to explore the impacts of 2 years of elevated atmospheric [CO2] and N addition on the growth, physiological characteristics and chemical compositions of five subtropical tree species in a cadmium (Cd)-contaminated environment. Results showed that N addition significantly increased concentration of leaf N and protein in five tree species and also decreased payback time (PBT) and leaf carbon:nitrogen ratios and increased tree relative height growth rate (RGR-H) and basal diameter growth rate (RGR-B) in Liquidambar formosana Hance and Syzygium hainanense Chang et Miau. Elevated [CO2] increased leaf maximum photosynthetic rate (Amax) and concentration of total non-structural carbohydrates and shortened PBT to offset the negative effect of Cd contamination on RGR-B in Acacia auriculiformis A. Cunn. ex Benth. The combined effects of elevated [CO2] and N addition did not exceed their separate effects on RGR-H and RGR-B in Castanopsis hystrix Hook. f. & Thomson ex A. DC. and Cinnamomum camphora (L.) presl. The addition of N significantly increased the concentration of leaf Cd by 162.1% and 338.0%, and plant Cd bio-concentration factor by 464% and 861% in C. hystrix and C. camphora, respectively, compared with only Cd addition. Among the five tree species, the decrease in PBT and the increase in Amax, RGR-B and concentrations of leaf protein in response to N and Cd addition under elevated [CO2] were on average 86.7% higher in A. auriculiformis than other species, suggesting that the mitigation of the negative effects of Cd pollution by elevated [CO2] and N addition among five species was species-specific. Overall, we concluded that N addition and elevated [CO2] reduced Cd toxicity and increased the growth rate in A. auriculiformis, S. hainanense and L. formosana, while it maintained the growth rate in C. hystrix and C. camphora by differently increasing photosynthetic rate, altering the leaf chemical compositions and shortening PBT.

Prediction and Construction of Energetic Materials Based on Machine Learning Methods.

Energetic materials (EMs) are the core materials of weapons and equipment. Achieving precise molecular design and efficient green synthesis of EMs has long been one of the primary concerns of researchers around the world. Traditionally, advanced materials were discovered through a trial-and-error processes, which required long research and development (R&D) cycles and high costs. In recent years, the machine learning (ML) method has matured into a tool that compliments and aids experimental studies for predicting and designing advanced EMs. This paper reviews the critical process of ML methods to discover and predict EMs, including data preparation, feature extraction, model construction, and model performance evaluation. The main ideas and basic steps of applying ML methods are analyzed and outlined. The state-of-the-art research about ML applications in property prediction and inverse material design of EMs is further summarized. Finally, the existing challenges and the strategies for coping with challenges in the further applications of the ML methods are proposed.

Prediction of Individual Analgesic Response to Intravenous Lidocaine in Painful Diabetic Peripheral Neuropathy: A Randomized, Placebo-controlled, Crossover Trial.

OBJECTIVES: Intravenous lidocaine can alleviate painful diabetic peripheral neuropathy (DPN) in some patients. Whether quantitative sensory testing (QST) can identify treatment responders has not been prospectively tested. MATERIALS AND METHODS: This was a prospective, randomized, double-blind, crossover, placebo-controlled trial comparing intravenous lidocaine to normal saline (placebo) for painful DPN. Thirty-four participants with painful DPN were enrolled and administered intravenous lidocaine (5 mg/kg ideal body weight) or placebo as a 40-minute infusion, after a battery of QST parameters were tested on the dorsal foot, with a 3-week washout period between infusions. RESULTS: Thirty-one participants completed both study sessions and were included in the final analysis. Lidocaine resulted in a 51% pain reduction 60 to 120 minutes after infusion initiation, as assessed on a 0 to 10 numerical rating scale, while placebo resulted in a 33.5% pain reduction (difference=17.6%, 95% confidence interval [CI], 1.9%-33.3%, P=0.03). Neither mechanical pain threshold, heat pain threshold, or any of the other measured QST parameters predicted the response to treatment. Lidocaine administration reduced mean Neuropathic Pain Symptom Inventory paresthesia/dysesthesia scores when compared with placebo by 1.29 points (95% CI, -2.03 to -0.55, P=0.001), and paroxysmal pain scores by 0.84 points (95% CI, -1.62 to -0.56, P=0.04), without significant changes in burning, pressing or evoked pain subscores. DISCUSSION: While some participants reported therapeutic benefit from lidocaine administration, QST measures alone were not predictive of response to treatment. Further studies, powered to test more complex phenotypic interactions, are required to identify reliable predictors of response to pharmacotherapy in patients with DPN.

Effects of elevated CO2 concentration and nitrogen addition on foliar phosphorus fractions of Mikania micranatha and Chromolaena odorata under low phosphorus availability.

Invasive plants rapidly spread in habitats with low soil phosphorus (P) availability and have triggered a sharp decline in the diversity of native species. However, no studies have explored how widespread invasive species acclimate to low soil P availability via changing foliar P fractions, especially under elevated atmospheric CO2 concentrations ([CO2 ]) and nitrogen (N) deposition. Here, an open-top chamber experiment was conducted to explore the effect of nutrient addition and elevated [CO2 ] on leaf traits and foliar functional P fractions (i.e., Pi, metabolite P, lipid P, nucleic acid P, and residual P) of two aggressive invasive species (Mikania micranatha and Chromolaena odorata). We found that foliar N/P ratios were more than 20, and P addition significantly increased plant biomass. Both results indicated P-limited plant growth at our studied site. Elevated [CO2 ], N and N + P addition greatly increased plant biomass, photosynthetic rates, and photosynthetic P-use efficiency (PPUE) in invasive species, but PPUE decreased with increasing P addition. Nitrogen addition slightly decreased the concentration of leaf total P, decreased foliar residual P, but increased metabolite P concentrations in invasive species. Similar changes in foliar P fractions were found under N + P addition. Phosphorus addition increased foliar P concentrations, which was strongly correlated with an increase in metabolite P concentrations in invasive species. Elevated [CO2 ] alleviated these effects and increased PPUE. The present results suggest that future elevated [CO2 ] and N deposition allow the invasive species to acclimate to low soil P availability and support their successful invasion by greatly reducing P allocation to non-metabolite foliar P fractions (i.e., nucleic acid P and residual P) to meet their demand of metabolite P for photosynthesis and exhibit a high PPUE.

Administration in fed state but not controlled release in the colon increases oral bioavailability of DF030263, a promising drug candidate for chronic lymphocytic leukemia.

For treatment of chronic cancers, the oral administration route is preferred as it provides numerous advantages over other delivery routes. However, these benefits of oral chemotherapy can be limited due to unfavorable pharmacokinetics. Accordingly, pharmacokinetic development of chemotherapeutic agents is crucial to the improvement of cancer treatment. In this study, assessment and optimization of biopharmaceutical properties of a promising drug candidate for cyclin-dependent kinase 9 (CDK9) inhibitor (DF030263) was performed to promote oral delivery. Oral bioavailability of DF030263 in fasted rats was 23.8%, and a distinct double-peak phenomenon was observed. A two-site absorption windows mechanism was proposed as a possible explanation to the phenomenon. The two-site absorption window hypothesis was supported by in vitro solubility assays in biorelevant fluids with different pH levels, as well as by in silico simulation by GastroPlus™. Controlled release to the colon was conducted in rats in order to exploit the colonic absorption window but did not improve the oral bioavailability. On the other hand, oral administration at postprandial conditions in rats (performed based on the high in vitro solubility in fed state simulated fluid and reduced pH-dependency) resulted in an almost 3-fold increase in bioavailability to 63.6%. In conclusion, this study demonstrates an efficient in vitro-in vivo-in silico drug development approach for improving the oral bioavailability of DF030263, a promising candidate for the treatment of chronic lymphocytic leukemia.

Interspecies prediction of pharmacokinetics and tissue distribution of doxorubicin by physiologically-based pharmacokinetic modeling.

The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK) model to describe and predict whole-body disposition of doxorubicin following intravenous administration. The PBPK model was established using previously published data in mice and included 10 tissue compartments: lungs, heart, brain, muscle, kidneys, pancreas, intestine, liver, spleen, adipose tissue, and plasma. Individual tissues were described by either perfusion-limited or permeability-limited models. All parameters were simultaneously estimated and the final model was able to describe murine data with good precision. The model was used for predicting doxorubicin disposition in rats, rabbits, dogs, and humans using interspecies scaling approaches and was qualified using plasma and tissue observed data. Reasonable prediction of the plasma pharmacokinetics and tissue distribution was achieved across all species. In conclusion, the PBPK model developed based on a rich dataset obtained from mice, was able to reasonably predict the disposition of doxorubicin in other preclinical species and humans. Applicability of the model for special populations, such as patients with hepatic impairment, was also demonstrated. The proposed model will be a valuable tool for optimization of exposure profiles of doxorubicin in human patients.

Effects of forest conversion on carbon-degrading enzyme activities in subtropical China.

The mineralization of soil organic carbon (SOC) is primarily mediated by carbon (C) degrading enzyme. In the current study, we determined how the activities of four soil C-degrading enzymes, the hydrolases ß-glucosidase (BG) and cellobiohydrolase (CBH) and the oxidases polyphenol oxidase (PPO) and peroxidase (POD), responded to forest conversion of natural broadleaf forests (BF) to secondary forests (SF) and plantation forests (PF) in subtropical China. We also quantified SOC, dissolved organic C (DOC), permanganate oxidase organic C (PXC), recalcitrant C (RC), microbial biomass C (MBC), mineral-associated C (MOC), soil particle-sizes distribution, pH, and moisture content, and C: nitrogen (N) ratio. Results showed that, the activities of all four C-degrading enzymes (BG, CBH, PPO and POD) decreased by 23.1, 9.5, 6.9 and 1.8%, respectively by forest conversion of BF to SF and 30.5, 15.3, 28.1 and 27.8%, respectively by conversion of BF to PF and were higher in the topsoil than in the subsoil. Relative to SF and PF, BF had higher hydrolase activities, which were related to its higher concentrations of MBC, DOC, and PXC, and to its lower C:N ratio. The BF also had higher oxidase activities, which were related to its higher concentrations of MBC, RC, and MOC, and to its lower C:N ratio. PF had higher specific enzyme activities (i.e., enzyme activities per unit of SOC) than BF and SF, indicating faster C turnover rates in PF. In addition to being affected by the concentrations of SOC and SOC components, forest conversion-induced changes in soil enzyme activities were affected by clay content and soil moisture content. These results revealed the different underlying mechanisms between soil hydrolases and oxidases in their responses to forest conversion.

Effects of elevated atmospheric CO2 and nitrogen deposition on leaf litter and soil carbon degrading enzyme activities in a Cd-contaminated environment: A mesocosm study.

Rising atmospheric CO2 concentration and nitrogen (N) deposition are changing terrestrial carbon (C) cycle; however, little has been known about such impacts in a heavy-metal-contaminated environment. This study conducted an open-top chamber experiment to explore the impacts of rising atmospheric CO2 concentration and N deposition on the leaf litter and soil C cycle in cadmium (Cd)-contaminated environment. The experiment include five treatments: control, Cd (30 g ha-1 yr-1) addition, Cd addition under elevated CO2 (700 ppm CO2), Cd and N(100 kg ha-1 yr-1) additions, and Cd and N additions under elevated CO2, with three replicates per treatment. Leaf litter and soil C cycle were indexed by microbial biomass C concentration and the activities of four key C-degrading enzyme (ß-glucosidase (BG), cellobiohydrolase (CBH), polyphenol oxidase (PPO), and peroxidase (POD)) in litter and soil. Results showed that, after one year treatment, Cd addition negatively affected the activities of all four C-degrading enzyme in litter and soil; while elevated CO2 and N addition essentially alleviated these negative effects. Elevated CO2 and N addition increased C-degrading enzyme activities more of the non-legume (i.e., Cinnamomum camphora) litter than those of the legume (i.e., Acacia auriculiformis) litter. Elevated CO2, N addition, and Cd addition all affected C-degrading enzyme activities via their effects on the microbial biomass C concentration and C and N availability of the litter and soil samples. We suggest that rising atmospheric CO2 concentration and N deposition can offset the detrimental effect of Cd on the litter and soil C-degrading enzyme activities in forest ecosystems.

Prevention of paclitaxel-induced neuropathy by formulation approach.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicity in-vitro and in-vivo in comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 µg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 µg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 µg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs.

Physiologically-based modeling and interspecies prediction of paclitaxel pharmacokinetics.

The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol-Taxol®) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported paclitaxel plasma and tissue concentration-time data following single intravenous bolus administration of Taxol® to mice were used; and the PBPK model included plasma, liver, lungs, kidneys, spleen, heart, gastrointestinal tract, and remainder compartments. The final model resulted in a good description of the experimental plasma and tissues data in mice, where all tissues were represented by a single compartment, except the remainder that included two sub-compartments. The predictive performance of the PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of paclitaxel in rats and humans. The relationship between species body weights (mice, rats, rabbits, and humans) and plasma clearance was determined by power-based regression, and resulting allometric exponent was 0.86. The model demonstrated reasonable predictions of plasma and tissue paclitaxel concentration-time profiles in rats and plasma profiles in humans. The proposed PBPK model represents an important basis that can be further utilized for characterization of novel formulations of paclitaxel.

Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays.

In this study, Caco-2 permeability results from different laboratories were compared. Six different sets of apparent permeability coefficient (Papp) values reported in the literature were compared to experimental Papp obtained in our laboratory. The differences were assessed by determining the root mean square error (RMSE) values between the datasets, which reached levels as high as 0.581 for the training set compounds, i.e. ten compounds with known effective human permeability (Peff). The consequences of these differences in Papp for prediction of oral drug absorption were demonstrated by introducing the Papp into the absorption and pharmacokinetics simulation software application GastroPlus™ for prediction of the fraction absorbed (Fa) in humans using calibrated "user-defined permeability models". The RMSE were calculated to assess the differences between the simulated Fa and experimental values reported in the literature. The RMSE for Fa simulated with the permeability model calibrated using experimental Papp from our laboratory was 0.128. When the calibration was performed using Papp from literature datasets, the RMSE values for Fa were higher in all cases except one. This study shows quantitative lab-to-lab variability of Caco-2 permeability results and the potential consequences this can have in the use of these results for predicting intestinal absorption of drugs.