Comprehensive utilization of waste hemicelluloses during ethanol production to increase lactic acid yield: from pretreatment to fermentation

Background

Reducing the cost of producing cellulosic ethanol is essential for the industrialization of biorefinery. Several processes are currently under investigation, but few of these techniques are entirely satisfactory in terms of competitive cost or environmental impact. In this study, a new ethanol and lactic acid (LA) coproduction is proposed. The technique involved addition of waste alkaline peroxide pretreated hydrolysate (mainly LA and hemicelluloses) to the reaction mixture after ethanol fermentation (mainly LA and xylose) to reduce the ethanol production cost.

Results

The following processes were investigated to optimize LA production: no addition of hemicelluloses or hydrolysate, addition of recycled hemicelluloses, and addition of concentrated hydrolysate. The addition of concentrated hydrolysate at 48 hours, which resulted in a maximum LA concentration of 22.3 g/L, was the most environment-friendly and cost-effective process. After the improved fermentation, 361 mg LA and 132 mg ethanol were produced from 1 g of raw poplar wood. That is, the production of one gallon of ethanol produced $9 worth of LA.

Conclusions

The amount of LA produced from the pretreated hydrolysate and reaction mixture after ethanol fermentation cannot be underestimated. The recovery of hydrolysate rich in LA and hemicelluloses (or xylose) significantly improved LA yield and further reduced the ethanol production cost.

     

Aerobic and sequential anaerobic fermentation to produce xylitol and ethanol using non-detoxified acid pretreated corncob

Background

For economical bioethanol production from lignocellulosic materials, the major technical challenges to lower the production cost are as follows: (1) The microorganism should use efficiently all glucose and xylose in the lignocellulose hydrolysate. (2) The microorganism should have high tolerance to the inhibitors present in the lignocellulose hydrolysate. The aim of the present work was to combine inhibitor degradation, xylitol fermentation, and ethanol production using a single yeast strain.

Results

A new process of integrated aerobic xylitol production and anaerobic ethanol fermentation using non-detoxified acid pretreated corncob by Candida tropicalis W103 was proposed. C. tropicalis W103 is able to degrade acetate, furfural, and 5-hydromethylfurfural and metabolite xylose to xylitol under aerobic conditions, and the aerobic fermentation residue was used as the substrate for ethanol production by anaerobic simultaneous saccharification and fermentation. With 20% substrate loading, furfural and 5-hydroxymethylfurfural were degraded totally after 60 h aerobic incubation. A maximal xylitol concentration of 17.1 g l^-1 was obtained with a yield of 0.32 g g^-1 xylose. Then under anaerobic conditions with the addition of cellulase, 25.3 g l^-1 ethanol was produced after 72 h anaerobic fermentation, corresponding to 82% of the theoretical yield.

Conclusions

Xylitol and ethanol were produced in Candida tropicalis W103 using dual-phase fermentations, which comprise a changing from aerobic conditions (inhibitor degradation and xylitol production) to anaerobic simultaneous saccharification and ethanol fermentation. This is the first report of integrated xylitol and ethanol production from non-detoxified acid pretreated corncob using a single microorganism.

     

A novel strategy for production of ethanol and recovery of xylose from simulated corncob hydrolysate

Objectives

To develop a xylose-nonutilizing Escherichia coli strain for ethanol production and xylose recovery.

Results

Xylose-nonutilizing E. coli CICIM B0013-2012 was successfully constructed from E. coli B0013-1030 (pta-ack, ldhA, pflB, xylH) by deletion of frdA, xylA and xylE. It exhibited robust growth on plates containing glucose, arabinose or galactose, but failed to grow on xylose. The ethanol synthesis pathway was then introduced into B0013-2012 to create an ethanologenic strain B0013-2012PA. In shaking flask fermentation, B0013-2012PA fermented glucose to ethanol with the yield of 48.4 g/100 g sugar while xylose remained in the broth. In a 7-l bioreactor, B0013-2012PA fermented glucose, galactose and arabinose in the simulated corncob hydrolysate to 53.4 g/l ethanol with the yield of 48.9 g/100 g sugars and left 69.6 g/l xylose in the broth, representing 98.6% of the total xylose in the simulated corncob hydrolysate.

Conclusions

By using newly constructed strain B0013-2012PA, we successfully developed an efficient bioprocess for ethanol production and xylose recovery from the simulated corncob hydrolysate.

     

Strategies to assess and optimize stability of endogenous amines during cerebrospinal fluid sampling

Introduction

Metabolic profiling of cerebrospinal fluid (CSF) is a promising technique for studying brain diseases. Measurements should reflect the in vivo situation, so ex vivo metabolism should be avoided.

Objective

To investigate the effects of temperature (room temperature vs. 4 °C), centrifugation and ethanol, as anti-enzymatic additive during CSF sampling on concentrations of glutamic acid, glutamine and other endogenous amines.

Methods

CSF samples from 21 individuals were processed using five different protocols. Isotopically-labeled alanine, isoleucine, glutamine, glutamic acid and dopamine were added prior to sampling to trace any degradation. Metabolomics analysis of endogenous amines, isotopically-labeled compounds and degradation products was performed with a validated LC–MS method.

Results

Thirty-six endogenous amines were quantified. There were no statistically significant differences between sampling protocols for 31 out of 36 amines. For GABA there was primarily an effect of temperature (higher concentrations at room temperature than at 4 °C) and a small effect of ethanol (lower concentrations if added) due to possible degradation. O-phosphoethanolamine concentrations were also lower when ethanol was added. Degradation of isotopically-labeled compounds (e.g. glutamine to glutamic acid) was minor with no differences between protocols.

Conclusion

Most amines can be considered stable during sampling, provided that samples are cooled immediately to 4 °C, centrifuged, and stored at ??80 °C within 2 h. The effect of ethanol addition for more unstable metabolites needs further investigation. This was the first time that labeled compounds were used to monitor ex vivo metabolism during sampling. This is a useful strategy to study the stability of other metabolites of interest.

     

Combined ensiling and hydrothermal processing as efficient pretreatment of sugarcane bagasse for 2G bioethanol production

Background

Ensiling cannot be utilized as a stand-alone pretreatment for sugar-based biorefinery processes but, in combination with hydrothermal processing, it can enhance pretreatment while ensuring a stable long-term storage option for abundant but moist biomass. The effectiveness of combining ensiling with hydrothermal pretreatment depends on biomass nature, pretreatment, and silage conditions.

Results

In the present study, the efficiency of the combined pretreatment was assessed by enzymatic hydrolysis and ethanol fermentation, and it was demonstrated that ensiling of sugarcane bagasse produces organic acids that can partly degrade biomass structure when in combination with hydrothermal treatment, with the consequent improvement of the enzymatic hydrolysis of cellulose and of the overall 2G bioethanol process efficiency. The optimal pretreatment conditions found in this study were those using ensiling and/or hydrothermal pretreatment at 190 °C for 10 min as this yielded the highest overall glucose recovery yield and ethanol yield from the raw material (0.28–0.30 g/g and 0.14 g/g, respectively).

Conclusion

Ensiling prior to hydrothermal pretreatment offers a controlled solution for wet storage and long-term preservation for sugarcane bagasse, thus avoiding the need for drying. This preservation method combined with long-term storage practice can be an attractive option for integrated 1G/2G bioethanol plants, as it does not require large capital investments or energy inputs and leads to comparable or higher overall sugar recovery and ethanol yields.

     

Co-generation of ethanol and <Emphasis Type="SmallCaps">l</Emphasis>-lactic acid from corn stalk under a hybrid process

Background

Corn stover, as one important lignocellulosic material, has characteristics of low price, abundant output and easy availability. Using corn stover as carbon source in the fermentation of valuable organic chemicals contributes to reducing the negative environmental problems and the cost of production. In ethanol fermentation based on the hydrolysate of corn stover, the conversion rate of fermentable sugars is at a low level because the native S. cerevisiae does not utilize xylose. In order to increase the conversion rate of fermentable sugars deriving from corn stover, an effective and energy saving biochemical process was developed in this study and the residual xylose after ethanol fermentation was further converted to l-lactic acid.

Results

In the hybrid process based on the hydrolysate of corn stover, the ethanol concentration and productivity reached 50.50 g L^?1 and 1.84 g L^?1 h^?1, respectively, and the yield of ethanol was 0.46 g g^?1. The following fermentation of l-lactic acid provided a product titer of 21.50 g L^?1 with a productivity of 2.08 g L^?1 h^?1, and the yield of l-lactic acid was 0.76 g g^?1. By adopting a blank aeration before the inoculation of B. coagulans LA1507 and reducing the final cell density, the l-lactic acid titer and yield reached 24.25 g L^?1 and 0.86 g g^?1, respectively, with a productivity of 1.96 g L^?1 h^?1.

Conclusions

In this work, the air pumped into the fermentor was used as both the carrier gas for single-pass gas stripping of ethanol and the oxygen provider for the aerobic growth of B. coagulans LA1507. Ethanol was effectively separated from the fermentation broth, while the residual medium containing xylose was reused for l-lactic acid production. As an energy-saving and environmental-friendly process, it introduced a potential way to produce bioproducts under the concept of biorefinery, while making full use of the hydrolysate of corn stover.

     

Corneal Collagen Cross-Linking for the Management of Mycotic Keratitis

Purpose

To evaluate the efficiency of corneal collagen cross-linking (CXL) in addition to topical voriconazole in cases with mycotic keratitis.

Design

Retrospective case series in a tertiary university hospital.

Participants

CXL was performed on 13 patients with mycotic keratitis who presented poor or no response to topical voriconazole treatment.

Methods

The clinical features, symptoms, treatment results and complications were recorded retrospectively. The corneal infection was graded according to the depth of infection into the stroma (from grade 1 to grade 3). The visual analogue scale was used to calculate the pain score before and 2 days after surgery.

Main Outcome Measures

Grade of the corneal infection.

Results

Mean age of 13 patients (6 female and 7 male) was 42.4 ± 17.7 years (20–74 years). Fungus was demonstrated in culture (eight patients) or cytological examination (five patients). Seven of the 13 patients (54%) were healed with topical voriconazole and CXL adjuvant treatment in 26 ± 10 days (15–40 days). The remaining six patients did not respond to CXL treatment; they initially presented with higher grade ulcers. Pre- and post-operative pain score values were 8 ± 0.8 and 3.5 ± 1, respectively (p < 0.05).

Conclusions

The current study suggests that adjunctive CXL treatment is effective in patients with small and superficial mycotic ulcers. These observations require further research by large randomized clinical trials.

     

Short-term adaptation during propagation improves the performance of xylose-fermenting <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis> in simultaneous saccharification and co-fermentation

Background

Inhibitors that are generated during thermochemical pretreatment and hydrolysis impair the performance of microorganisms during fermentation of lignocellulosic hydrolysates. In omitting costly detoxification steps, the fermentation process relies extensively on the performance of the fermenting microorganism. One attractive option of improving its performance and tolerance to microbial inhibitors is short-term adaptation during propagation. This study determined the influence of short-term adaptation on the performance of recombinant Saccharomyces cerevisiae in simultaneous saccharification and co-fermentation (SSCF). The aim was to understand how short-term adaptation with lignocellulosic hydrolysate affects the cell mass yield of propagated yeast and performance in subsequent fermentation steps. The physiology of propagated yeast was examined with regard to viability, vitality, stress responses, and upregulation of relevant genes to identify any links between the beneficial traits that are promoted during adaptation and overall ethanol yields in co-fermentation.

Results

The presence of inhibitors during propagation significantly improved fermentation but lowered cell mass yield during propagation. Xylose utilization of adapted cultures was enhanced by increasing amounts of hydrolysate in the propagation. Ethanol yields improved by over 30 % with inhibitor concentrations that corresponded to ≥2.5 % water-insoluble solids (WIS) load during the propagation compared with the unadapted culture. Adaptation improved cell viability by >10 % and increased vitality by >20 %. Genes that conferred resistance against inhibitors were upregulated with increasing amounts of inhibitors during the propagation, but the adaptive response was not associated with improved ethanol yields in SSCF. The positive effects in SSCF were observed even with adaptation at inhibitor concentrations that corresponded to 2.5 % WIS. Higher amounts of hydrolysate in the propagation feed further improved the fermentation but increased the variability in fermentation outcomes and resulted in up to 20 % loss of cell mass yield.

Conclusions

Short-term adaptation during propagation improves the tolerance of inhibitor-resistant yeast strains to inhibitors in lignocellulosic hydrolysates and improves their ethanol yield in fermentation and xylose-fermenting capacity. A low amount of hydrolysate (corresponding to 2.5 % WIS) is optimal, whereas higher amounts decrease cell mass yield during propagation.

     

Optimization of NaOH-catalyzed steam pretreatment of empty fruit bunch

Background

Empty fruit bunch (EFB) has many advantages, including its abundance, the fact that it does not require collection, and its year-round availability as a feedstock for bioethanol production. But before the significant costs incurred in ethanol production from lignocellulosic biomass can be reduced, an efficient sugar fractionation technology has to be developed. To that end, in the present study, an NaOH-catalyzed steam pretreatment process was applied in order to produce ethanol from EFB more efficiently.

Results

The EFB pretreatment conditions were optimized by application of certain pretreatment variables such as, the NaOH concentrations in the soaking step and, in the steam step, the temperature and time. The optimal conditions were determined by response surface methodology (RSM) to be 3% NaOH for soaking and 160°C, 11 min 20 sec for steam pretreatment. Under these conditions, the overall glucan recovery and enzymatic digestibility were both high: the glucan and xylan yields were 93% and 78%, respectively, and the enzymatic digestibility was 88.8% for 72 h using 40 FPU/g glucan. After simultaneous saccharification and fermentation (SSF), the maximum ethanol yield and concentration were 0.88 and 29.4 g/l respectively.

Conclusions

Delignification (>85%) of EFB was an important factor in enzymatic hydrolysis using CTec2. NaOH-catalyzed steam pretreatment, which can remove lignin efficiently and requires only a short reaction time, was proven to be an effective pretreatment technology for EFB. The ethanol yield obtained by SSF, the key parameter determining the economics of ethanol, was 18% (w/w), equivalent to 88% of the theoretical maximum yield, which is a better result than have been reported in the relevant previous studies.

     

Selective oxidation of UDP-glucose to UDP-glucuronic acid using permeabilized <Emphasis Type="Italic">Schizosaccharomyces pombe</Emphasis> expressing human UDP-glucose 6-dehydrogenase

Objectives

To use permeabilized cells of the fission yeast, Schizosaccharomyces pombe, that expresses human UDP-glucose 6-dehydrogenase (UGDH, EC 1.1.1.22), for the production of UDP-glucuronic acid from UDP-glucose.

Results

In cell extracts no activity was detected. Therefore, cells were permeabilized with 0.3 % (v/v) Triton X-100. After washing away all low molecular weight metabolites, the permeabilized cells were directly used as whole cell biocatalyst. Substrates were 5 mM UDP-glucose and 10 mM NAD⁺. Divalent cations were not added to the reaction medium as they promoted UDP-glucose hydrolysis. With this reaction system 5 mM UDP-glucose were converted into 5 mM UDP-glucuronic acid within 3 h.

Conclusions

Recombinant permeabilized cells of S. pombe can be used to synthesize UDP-glucuronic acid with 100 % yield and selectivity.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

Butyric acid production from red algae by a newly isolated <Emphasis Type="Italic">Clostridium</Emphasis> sp. S1

Objective

To produce butyric acid from red algae such as Gelidium amansii in which galactose is a main carbohydrate, microorganisms utilizing galactose and tolerating inhibitors in hydrolysis including levulinic acid and 5-hydroxymethylfurfural (HMF) are required.

Results

A newly isolated bacterium, Clostridium sp. S1 produced butyric acid not only from galactose as the sole carbon source but also from a mixture of galactose and glucose through simultaneous utilization. Notably, Clostridium sp. S1 produced butyric acid and a small amount of acetic acid with the butyrate:acetate ratio of 45.4:1 and it even converted acetate to butyric acid. Clostridium sp. S1 tolerated 0.5–2 g levulinic acid/l and recovered from HMF inhibition at 0.6–2.5 g/l, resulting in 85–92 % butyric acid concentration of the control culture. When acid-pretreated G. amansii hydrolysate was used, Clostridium sp. S1 produced 4.83 g butyric acid/l from 10 g galactose/l and 1 g glucose/l.

Conclusion

Clostridium sp. S1 produces butyric acid from red algae due to its characteristics in sugar utilization and tolerance to inhibitors, demonstrating its advantage as a red algae-utilizing microorganism.

     

Exploration of serum biomarkers for predicting the response to Inchinkoto (ICKT), a Japanese traditional herbal medicine

Introduction

In patients with obstructive jaundice, biliary drainage sometimes fails to result in improvement. A pharmaceutical-grade choleretic herbal medicine, Inchinkoto (ICKT), has been proposed to exert auxiliary effects on biliary drainage; however, its effects are variable among patients.

Objectives

The aim of this study is to explore serum biomarkers that are associated with pharmaceutical efficacy of ICKT.

Methods

Obstructive jaundice patients who underwent external biliary decompression were enrolled (n?=?37). ICKT was given orally 3 times a day at daily dose of 7.5 g. Serum and bile samples were collected before, 3 h after, and 24 h after ICKT administration. The concentrations of total bilirubin, direct bilirubin, and total bile acid in bile specimens were measured. Metabolites in serum samples were comprehensively profiled using LC–MS/MS and GC–MS/MS. Pharmacokinetic analysis of major ICKT components was also performed.

Results

ICKT administration significantly decreased serum ALT and increased bile volume after 24 h. The serum concentrations of ICKT components were not well correlated with the efficacy of ICKT. However, the ratio of 2-hydroxyisobutyric acid to arachidonic acid and the ratio of glutaric acid to niacinamide, exhibited good performance as biomarkers for the efficacy of ICKT on bile flow and ALT, respectively. Additionally, comprehensive correlation analysis revealed that serum glucuronic acid was highly correlated with serum total bilirubin, suggesting that this metabolite may be deeply involved in the pathogenesis of jaundice.

Conclusions

The present study indicates that ICKT is efficacious and provides candidates for predicting ICKT efficacy. Further validation studies are warranted.

     

Bile acid quantification of 20 plasma metabolites identifies lithocholic acid as a putative biomarker in Alzheimer’s disease

Introduction

There is still a clear need for a widely available, inexpensive and reliable method to diagnose Alzheimer’s disease (AD) and monitor disease progression. Liquid chromatography–mass spectrometry (LC-MS) is a powerful analytic technique with a very high sensitivity and specificity.

Objectives

The aim of the present study is to measure concentrations of 20 bile acids using the novel Kit from Biocrates Life Sciences based on LC-MS technique.

Methods

Twenty bile acid metabolites were quantitatively measured in plasma of 30 cognitively healthy subjects, 20 patients with mild cognitive impairment (MCI) and 30 patients suffering from AD.

Results

Levels of lithocholic acid were significantly enhanced in plasma of AD patients (50?±?6 nM, p?=?0.004) compared to healthy controls (32?±?3 nM). Lithocholic acid plasma levels of MCI patients (41?±?4 nM) were not significantly different from healthy subjects or AD patients. Levels of glycochenodeoxycholic acid, glycodeoxycholic acid and glycolithocholic acid were significantly higher in AD patients compared to MCI patients (p?<?0.05). All other cholic acid metabolites were not significantly different between healthy subjects, MCI patients and AD patients. ROC analysis shows an overall accuracy of about 66%. Discriminant analysis was used to classify patients and we found that 15/23 were correctly diagnosed. We further showed that LCA levels increased by about 3.2 fold when healthy subjects converted to AD patients within a 8–9 year follow up period. Pathway analysis linked these changes to a putative toxic cholesterol pathway.

Conclusion

In conclusion, 4 bile acids may be useful to diagnose AD in plasma samples despite limitations in diagnostic accuracy.

     

R-wave synchronised atrial pacing in pediatric patients with postoperative junctional ectopic tachycardia: the atrioventricular interval investigated by computational analysis and clinical evaluation

Background

R-wave synchronised atrial pacing is an effective temporary pacing therapy in infants with postoperative junctional ectopic tachycardia. In the technique currently used, adverse short or long intervals between atrial pacing and ventricular sensing (AP–VS) may be observed during routine clinical practice.

Objectives

The aim of the study was to analyse outcomes of R-wave synchronised atrial pacing and the relationship between maximum tracking rates and AP–VS intervals.

Methods

Calculated AP–VS intervals were compared with those predicted by experienced pediatric cardiologist.

Results

A maximum tracking rate (MTR) set 10 bpm higher than the heart rate (HR) may result in undesirable short AP–VS intervals (minimum 83 ms). A MTR set 20 bpm above the HR is the hemodynamically better choice (minimum 96 ms). Effects of either setting on the AP–VS interval could not be predicted by experienced observers. In our newly proposed technique the AP–VS interval approaches 95 ms for HR > 210 bpm and 130 ms for HR < 130 bpm. The progression is linear and decreases strictly (? 0.4 ms/bpm) between the two extreme levels.

Conclusions

Adjusting the AP–VS interval in the currently used technique is complex and may imply unfavorable pacemaker settings. A new pacemaker design is advisable to allow direct control of the AP–VS interval.

     

Quantitative metabolome profiling reveals the involvement of the kynurenine pathway in influenza-associated encephalopathy

Introduction

Influenza-associated encephalopathy is a serious complication of influenza and is the most common form of acute encephalitis/encephalopathy in Japan. The number of reports from other countries is increasing, reflecting international recognition and concern.

Objectives

Identification of a specific biomarker could provide important clues about the pathophysiology of influenza-associated encephalopathy.

Methods

During the 2009–2011 flu seasons, 34 pediatric patients hospitalized with influenza complications, including influenza-associated encephalopathy, were enrolled in the study. Serum samples were collected during the acute and convalescent phases of disease. Patients were classified into encephalopathy (n = 12) and non-encephalopathy (n = 22) groups. Serum metabolites were identified and quantified by capillary electrophoresis coupled with time-of-flight mass spectrometry. Quantified data were evaluated for comparative analysis. Subsequently, a total of 55 patients with or without encephalopathy were enrolled for absolute quantification of serum kynurenine and quinolinic acid.

Results

Based on m/z values and migration times, 136 metabolites were identified in serum samples. During the acute phase of disease, three metabolites (succinic acid, undecanoic acid, and kynurenine) were significantly higher, and two other metabolites (decanoic acid and cystine) were significantly lower, in the encephalopathy group compared to the non-encephalopathy group (p = 0.012, 0.022, 0.044, 0.038, 0.046, respectively). In a larger patient group, serum kynurenine and its downstream product in tryptophan metabolism, quinolinic acid, a known neurotoxin, were significantly higher in the encephalopathy than the non-encephalopathy without febrile seizure group.

Conclusion

Comprehensive metabolite profiles revealed five metabolites as potential biomarkers for influenza-associated encephalopathy; the tryptophan–kynurenine metabolic process could be associated with its pathophysiology.

     

Carbon catabolite repression in <Emphasis Type="Italic">Thermoanaerobacterium saccharolyticum</Emphasis>

Background

The thermophilic anaerobe Thermoanaerobacterium saccharolyticum is capable of directly fermenting xylan and the biomass-derived sugars glucose, cellobiose, xylose, mannose, galactose and arabinose. It has been metabolically engineered and developed as a biocatalyst for the production of ethanol.

Results

We report the initial characterization of the carbon catabolite repression system in this organism. We find that sugar metabolism in T. saccharolyticum is regulated by histidine-containing protein HPr. We describe a mutation in HPr, His15Asp, that leads to derepression of less-favored carbon source utilization.

Conclusion

Co-utilization of sugars can be achieved by mutation of HPr in T. saccharolyticum. Further manipulation of CCR in this organism will be instrumental in achieving complete and rapid conversion of all available sugars to ethanol.

     

Prediction of intravenous busulfan clearance by endogenous plasma biomarkers using global pharmacometabolomics

Introduction

High-dose busulfan (busulfan) is an integral part of the majority of hematopoietic cell transplantation conditioning regimens. Intravenous (IV) busulfan doses are personalized using pharmacokinetics (PK)-guided dosing where the patient’s IV busulfan clearance is calculated after the first dose and is used to personalize subsequent doses to a target plasma exposure. PK-guided dosing has improved patient outcomes and is clinically accepted but highly resource-intensive.

Objective

We sought to discover endogenous plasma biomarkers predictive of IV busulfan clearance using a global pharmacometabolomics-based approach

Methods

Using LC-QTOF, we analyzed 59 (discovery) and 88 (validation) plasma samples obtained before IV busulfan administration.

Results

In the discovery dataset, we evaluated the association of the relative abundance of 1885 ions with IV busulfan clearance and found 21 ions that were associated with IV busulfan clearance tertiles (r² ≥ 0.3). Identified compounds were deoxycholic acid and/or chenodeoxycholic acid, and linoleic acid. We used these 21 ions to develop a parsimonious seven-ion linear predictive model that accurately predicted IV busulfan clearance in 93 % (discovery) and 78 % (validation) of samples.

Conclusion

IV busulfan clearance was significantly correlated with the relative abundance of 21 ions, seven of which were included in a predictive model that accurately predicted IV busulfan clearance in the majority of the validation samples. These results reinforce the potential of pharmacometabolomics as a critical tool in personalized medicine, with the potential to improve the personalized dosing of drugs with a narrow therapeutic index such as busulfan.