Effect Of Interindividual Variability Research Articles

Factors and effects of inter-individual variability in silver birch phenology using dense LiDAR time-series

Comprehending and quantifying local variability in plant phenology, alongside its impacts on tree growth, is challenging due to spatially and temporally heterogeneous environmental factors that interact to affect phenological events and periods. Although previous studies have focused on the climatic factors driving phenological events at the stand level, the influences of competition, neighborhood characteristics, species richness, and water availability on plant phenology remain unclear. In the present paper, we used hourly terrestrial LiDAR surveys performed between April 2020 and April 2021 to investigate the influence of local factors (neighborhood and topography) on the phenology of silver birch trees (Betula pendula Roth.). We also examined how phenological events affect growth in tree height and crown area. All response and explanatory variables were estimated using LiDAR time-series data and a field survey campaign. Our findings demonstrate a high within-species variability in plant phenology that is controlled by biotic and abiotic characteristics of the ecosystem. We found that between tree variation in leaf burst, completion of the leaf growth and length of canopy growth period were affected by tree size, neighborhood species richness, level of suppression and competition, which potentially indicate plant responses to light availability. The beginning of senescence, completion of leaf drop, and length of autumn phenology were mostly affected by topographic water index, which reflects water availability and can be linked to nutrient availability and exposure to wind. Furthermore, we demonstrated that an earlier leaf burst, and delayed beginning of senescence were associated with larger absolute growth in canopy area but found no clear relationship between height growth and phenology. Our study highlights the capability of dense, high-quality LiDAR time-series to detect significant phenological variation among individuals of the same species within the same locality, demonstrating the potential of LiDAR time-series as a tool for understanding phenology and its impacts.

Effect of Interindividual Variability in Metabolic Clearance and Relative Bioavailability on Rifampicin Exposure in Tuberculosis Patients with and without HIV Co-Infection: Does Formulation Quality Matter?

The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetyl-rifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual variation in the exposure to RIF. Pharmacokinetic, clinical, and demographic data from TB patients with (TB-HIV+ group; n = 18) or without HIV (TB-HIV- group; n = 15) who were receiving RIF as part of a four-drug fixed-dose combination (FDC) regimen (RIF, isoniazid, pyrazinamide, and ethambutol) were analysed, along with the published literature data on the relative bioavailability of different formulations. A population pharmacokinetic model, including the formation of desRIF, was developed and compared to a model based solely on the parent drug. HIV co-infection does not alter the plasma exposure to RIF and the desRIF formation does not contribute to the observed variability in the RIF disposition. The relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard regimen with FDC tablets. Furthermore, participants weighting less than 50 kg do not reach the same RIF plasma exposure as compared to those weighting >50 kg. In conclusion, as no covariate was identified other than body weight on CL/F and Vd/F, low systemic exposure to RIF is likely to be caused by the low bioavailability of the formulation.

Physiologically-based pharmacokinetic modeling of dextromethorphan to investigate interindividual variability within CYP2D6 activity score groups.

This study provides a whole‐body physiologically‐based pharmacokinetic (PBPK) model of dextromethorphan and its metabolites dextrorphan and dextrorphan O‐glucuronide for predicting the effects of cytochrome P450 2D6 (CYP2D6) drug‐gene interactions (DGIs) on dextromethorphan pharmacokinetics (PK). Moreover, the effect of interindividual variability (IIV) within CYP2D6 activity score groups on the PK of dextromethorphan and its metabolites was investigated. A parent‐metabolite‐metabolite PBPK model of dextromethorphan, dextrorphan, and dextrorphan O‐glucuronide was developed in PK‐Sim and MoBi. Drug‐dependent parameters were obtained from the literature or optimized. Plasma concentration‐time profiles of all three analytes were gathered from published studies and used for model development and model evaluation. The model was evaluated comparing simulated plasma concentration‐time profiles, area under the concentration‐time curve from the time of the first measurement to the time of the last measurement (AUClast) and maximum concentration (Cmax) values to observed study data. The final PBPK model accurately describes 28 population plasma concentration‐time profiles and plasma concentration‐time profiles of 72 individuals from four cocktail studies. Moreover, the model predicts CYP2D6 DGI scenarios with six of seven DGI AUClast and seven of seven DGI Cmax ratios within the acceptance criteria. The high IIV in plasma concentrations was analyzed by characterizing the distribution of individually optimized CYP2D6 kcat values stratified by activity score group. Population simulations with sampling from the resulting distributions with calculated log‐normal dispersion and mean parameters could explain a large extent of the observed IIV. The model is publicly available alongside comprehensive documentation of model building and model evaluation.

Effect of inter-individual variability in human liver cytochrome P450 isozymes on cyclophosphamide-induced micronucleus formation

We investigated the relationship between metabolic activities of cytochrome P450 (CYP) isozymes present in microsomal fractions derived from the livers of 78 donors and micronucleus induction by cyclophosphamide (CPA). Consequently, a wide inter-individual variation in CYP activities was observed among the 78 donors. The CYP activities were partially correlated with the metabolic phenotypes predicted for the donors based on their single nucleotide polymorphisms. In addition, CPA induced micronucleus formation was seen for 47 out of 52 donors whose samples were tested with CPA doses ranging from 18.8 to 100 μg/mL. The CPA dose at which micronucleated cells were observed varied among the donors. Furthermore, a close correlation was identified between the catalytic activities of the CYP2B6, CYP2C9, CYP2C19, and CYP3A4 isozymes and micronucleus induction by CPA. To elucidate the mechanism underlying CPA-induced micronucleus formation in vitro tests were conducted on expression systems of CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Additionally, the metabolites of CPA generated by the expression systems were quantified by a liquid chromatography tandem mass spectrometer. Interestingly, several metabolites including the 4-hydroxyl form of CPA (4-OH-CPA) and phosphamide mustard were detected in the CYP2B6, CYP2C19, and CYP3A4 expression systems, but not in the CYP2C9 and CYP2D6 system. The presence of these metabolites was correlated with micronucleus induction by CPA. The absence of CPA metabolites in the CYP2C9 expression system might be associated with the lower 4-hydroxylase activity of this system.The present results suggest that inter-individual variability in the metabolic capacity of each donor was associated with potential micronucleus induction due to CPA. Additionally, CPA metabolites like 4-OH-CPA and phosphamide mustard produced by human CYP2B6, CYP2C9, CYP2C19, and CYP3A4 are suggested to be major determinants of micronucleus induction by CPA.

Equilibrative Nucleoside Transporter 1 (ENT1, SLC29A1) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta.

Abacavir is a preferred antiretroviral drug for preventing mother-to-child human immunodeficiency virus transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abacavir is a nucleoside-derived drug, we hypothesized that the nucleoside transporters, equilibrative nucleoside transporters (ENTs, SLC29A) and/or Na+-dependent concentrative nucleoside transporters (CNTs, SLC28A), may play a role in its passage across the placenta. To test this hypothesis, we performed uptake experiments using the choriocarcinoma-derived BeWo cell line, human fresh villous fragments, and microvillous plasma membrane (MVM) vesicles. Using endogenous substrates of nucleoside transporters, [3H]-adenosine (ENTs, CNT2, and CNT3) and [3H]-thymidine (ENTs, CNT1, and CNT3), we showed significant activity of ENT1 and CNT2 in BeWo cells, whereas experiments in the villous fragments and MVM vesicles, representing a model of the apical membrane of a syncytiotrophoblast, revealed only ENT1 activity. When testing [3H]-abacavir uptakes, we showed that of the nucleoside transporters, ENT1 plays the dominant role in abacavir uptake into placental tissues, whereas contribution of Na+-dependent transport, most likely mediated by CNTs, was observed only in BeWo cells. Subsequent experiments with dually perfused rat term placentas showed that Ent1 contributes significantly to overall [3H]-abacavir placental transport. Finally, we quantified the expression of SLC29A in first- and third-trimester placentas, revealing that SLC29A1 is the dominant isoform. Neither SLC29A1 nor SLC29A2 expression changed over the course of placental development, but there was considerable interindividual variability in their expression. Therefore, drug-drug interactions and the effect of interindividual variability in placental ENT1 expression on abacavir disposition into fetal circulation should be further investigated to guarantee safe and effective abacavir-based combination therapies in pregnancy.

Altered formation of the iron oxide nanoparticle-biocorona due to individual variability and exercise

Nanoparticles (NPs), introduced into a biological environment, accumulate a coating of biomolecules or biocorona (BC). Although the BC has toxicological and pharmacological consequences, the effects of inter-individual variability and exercise on NP-BC formation are unknown. We hypothesized that NPs incubated in plasma form distinct BCs between individuals, and exercise causes additional intra-individual alterations. 20 nm iron oxide (Fe3O4) NPs were incubated in pre- or post-exercise plasma ex vivo, and proteomics was utilized to evaluate BC components. Analysis demonstrated distinct BC formation between individuals, while exercise was found to enhance NP-BC complexity. Abundance differences of NP-BC proteins were determined between individuals and resulting from exercise. Differential human macrophage response was identified due to NP-BC variability. These findings demonstrate that individuals form unique BCs and that exercise influences NP-biomolecule interactions. An understanding of NP-biomolecule interactions is necessary for elucidation of mechanisms responsible for variations in human responses to NP exposures and/or nano-based therapies.

A reappraisal of the vital effect in cultured benthic foraminifer <I>Bulimina marginata</I> on Mg/Ca values: assessing temperature uncertainty relationships

Abstract. The reconstruction of past temperatures is often achieved through measuring the Mg/Ca value of foraminiferal test carbonate. The diversity in foraminiferal Mg/Ca–temperature calibrations suggests that there is also a biological control on this proxy. This study presents a new Mg/Ca–temperature calibration for the benthic foraminifer Bulimina marginata, based on cultures under a range of temperatures (4–14 °C). Measured Mg/Ca values for B. marginata correlate with temperature (Mg/Ca = (1.10 ± 0.10) e(0.045±0.009)T, R2 = 0.28 p < 0.01). The inter-individual variability is, however, also significant (standard deviation is 10–35% of the average). Before applying this or any calibration, the effect of the inter-individual variability on the accuracy of the Mg/Ca–temperature calibration has to be evaluated. The inter-individual variability is quantified and split into three components, namely (1) an analytical error, (2) an environmental effect and (3) a vital effect. The effect of inter-individual variability on the accuracy of Mg/Ca–temperature calibrations depends on the sensitivity of the calibration used and the number of individuals measured (temperature uncertainty = (0.33 · N−0.50)/sensitivity). The less sensitive a calibration, the greater is the impact of inter-individual variability, which can partly be circumvented by measuring more individuals. This study shows the link between inter-individual variability and sensitivity and quantifies their influence on the accuracy of Mg/Ca–temperature calibrations. Differences in the sensitivity of the Mg/Ca–temperature calibration of foraminifera may depend on the environmental conditions in which foraminifera live and their concurring ecological strategies.