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Pharmacokinetics, Disposition, and Biotransformation of [14C]Omecamtiv Mecarbil in Healthy Male Subjects after a Single Intravenous or Oral Dose.
Trivedi, A, Wahlstrom, J, Mackowski, M, Dutta, S, Lee, E
Drug metabolism and disposition: the biological fate of chemicals. 2021;(8):619-628
Abstract
Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that is currently in clinical development for the treatment of heart failure. The absorption and disposition of [14C]OM (60 µCi) were studied after a single intravenous infusion (35 mg over 1 hour) or oral solution dose (35 mg) in 14 healthy male subjects. Mean recovery of the administered [14C]OM dose was 85.1% and 86.5% over 336 hours for the intravenous and oral routes, respectively. After intravenous dosing, 47.8% and 37.3% of the dose was recovered in urine and feces, respectively; after oral dosing, 48.6% and 38.0% was recovered in urine and feces, respectively. Unchanged OM accounted for a minor percentage of radioactivity in urine (mean 7.7% of dose) and feces (mean 4.1% of dose) across all subjects. The major metabolites recovered in urine and feces were M3 (decarbamoylation product) and sequential metabolite M4 (lactam of M3), which accounted for means of 26.5% and 11.6% of the administered dose, respectively. The CYP4 family of enzymes was primarily responsible for the formation of M3 based on in vitro studies. Other metabolic pathways accounted for 14.9% of the administered dose. In pooled plasma, OM, M3, and M4 accounted for 83.8%, 6.0%, and 3.3% of the total [14C]OM-related materials. No other plasma metabolites constituted more than 3% of the administered dose. The bioavailability for OM solution was 93.5% after rapid and extensive absorption. SIGNIFICANCE STATEMENT This study characterized the absorption and disposition of OM, a novel small molecule being developed for the treatment of heart failure. OM was primarily cleared through metabolism by the CYP4 family through oxidative cleavage of a terminal carbamate moiety that resembles hydrolysis.
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Sotagliflozin Decreases Postprandial Glucose and Insulin Concentrations by Delaying Intestinal Glucose Absorption.
Powell, DR, Zambrowicz, B, Morrow, L, Beysen, C, Hompesch, M, Turner, S, Hellerstein, M, Banks, P, Strumph, P, Lapuerta, P
The Journal of clinical endocrinology and metabolism. 2020;(4):e1235-49
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Abstract
CONTEXT The effect of sotagliflozin (a dual sodium-glucose cotransporter [SGLT] 2 and SGLT1 inhibitor) on intestinal glucose absorption has not been investigated in humans. OBJECTIVE To measure rate of appearance of oral glucose (RaO) using a dual glucose tracer method following standardized mixed meals taken after single sotagliflozin or canagliflozin doses. SETTING Clinical research organization. DESIGN AND PARTICIPANTS In a double-blind, 3-period crossover study (NCT01916863), 24 healthy participants were randomized to 2 cohorts of 12 participants. Within each cohort, participants were randomly assigned single oral doses of either sotagliflozin 400 mg, canagliflozin 300 mg, or placebo on each of test days 1, 8, and 15. On test days, Cohort 1 had breakfast containing [6,6-2H2] glucose 0.25 hours postdose and lunch containing [1-2H1] glucose 5.25 hours postdose; Cohort 2 had breakfast containing no labeled glucose 0.25 hours postdose and lunch containing [6,6-2H2] glucose 4.25 hours postdose. All participants received a 10- to 15-hour continuous [U-13C6] glucose infusion starting 5 hours before their first [6,6-2H2] glucose-containing meal. MAIN OUTCOME RaO, postprandial glucose (PPG), and postprandial insulin. RESULTS Sotagliflozin and canagliflozin decreased area under the curve (AUC)0-1 hour and/or AUC0-2 hours for RaO, PPG, and insulin after breakfast and/or the 4.25-hour postdose lunch (P < .05 versus placebo). After the 5.25-hour postdose lunch, sotagliflozin lowered RaO AUC0-1 hour and PPG AUC0-5 hours versus both placebo and canagliflozin (P < .05). CONCLUSIONS Sotagliflozin delayed and blunted intestinal glucose absorption after meals, resulting in lower PPG and insulin levels, likely due to prolonged local inhibition of intestinal SGLT1 that persisted for ≥5 hours after dosing.
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Quantitative Measure of Intestinal Permeability Using Blue Food Coloring.
Angarita, SAK, Duarte, S, Russell, TA, Ruchala, P, Elliott, IA, Whitelegge, JP, Zarrinpar, A
The Journal of surgical research. 2019;:20-25
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Abstract
BACKGROUND Loss of intestinal barrier integrity plays a fundamental role in the pathogenesis of various gastrointestinal diseases and is implicated in the onset of sepsis and multiple organ failure. An array of methods to assess different aspects of intestinal barrier function suffers from lack of sensitivity, prolonged periods of specimen collection, or high expense. We have developed a technique to measure the concentration of the food dye FD&C Blue #1 from blood and sought to assess its utility in measuring intestinal barrier function in humans. MATERIALS AND METHODS Four healthy volunteers and 10 critically ill subjects in the intensive care unit were recruited in accordance with an institutional review board approved protocol. Subjects were given 0.5 mg/kg Blue #1 enterally as an aqueous solution of diluted food coloring. Five blood specimens were drawn per subject: 0 h (before dose), 1, 2, 4, and 8 h. After plasma isolation, organic extracts were analyzed by high-performance liquid chromatography/mass spectrometry detecting the presence of unmodified dye. RESULTS We found no baseline detectable absorption in healthy volunteers. After including the subjects in the intensive care unit, we compared dye absorption in the six subjects who met criteria for septic shock with the eight who did not. Septic patients demonstrated significantly greater absorption of Blue #1 after 2 h. CONCLUSIONS We have developed a novel, easy-to-use method to measure intestinal barrier integrity using a food grade dye detectable by mass spectrometry analysis of patient blood following oral administration.
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Measurement of intestinal permeability using lactulose and mannitol with conventional five hours and shortened two hours urine collection by two different methods: HPAE-PAD and LC-MSMS.
Musa, MA, Kabir, M, Hossain, MI, Ahmed, E, Siddique, A, Rashid, H, Mahfuz, M, Mondal, D, Ahmed, T, Petri, WA, et al
PloS one. 2019;(8):e0220397
Abstract
Urinary excretion of two orally-administered non-metabolizable sugars, lactulose and mannitol, is a valuable marker for evaluating intestinal permeability. Usually this test involves a time consuming procedure of about 5 hour's urine collection, which makes the test incompatible to some extent. As the results are expressed as the ratio of lactulose and mannitol recovered in urine within certain time, it may be possible to get similar result despite the reduced urine collection time of 2 hours. Moreover, different laboratories do the test by different methods, which make the results incomparable between laboratories. Here, we are also trying to find the correlation between results from most commonly used methods: HPAE-PAD and LC-MSMS. The lactulose: mannitol (LM) test was performed in a cohort of Bangladeshi infants considered at-risk for environmental enteropathy. 208 urine specimens from 104 (52 male and 52 female) infants were collected at 2 and 5 hours after LM solution administration and were tested for lactulose and mannitol by two different methods, one HPAE-PAD platform and another LC-MSMS platform. Median age of the children was 15.0 months (range 6.9 to 25.8 months) and their mean weight-for-age z-score was -0.92. A higher percentage of lactulose and mannitol recovery was found in 5 hours urine collection than in the corresponding 2 hours by both HPAE-PAD and LC-MSMS method, but when results were expressed as lactulose to mannitol ratio (LMR) there was no significant difference between 2 and 5 hours urine collection in both HPAE-PAD (P = 0.138) and LC-MSMS (P = 0.099) method. LMR based on 2 hours urine collection correlated well with LMR based on traditional 5 hours urine collection (Spearman's correlation coefficient 0.578 and 0.604 respectively for HPAE-PAD and LC-MSMS). In future, LM test to assess intestinal permeability in children can be simplified by shortening the urine collection time from 5 hours to 2 hours.
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A novel self-micro-emulsifying delivery system (SMEDS) formulation significantly improves the fasting absorption of EPA and DHA from a single dose of an omega-3 ethyl ester concentrate.
Qin, Y, Nyheim, H, Haram, EM, Moritz, JM, Hustvedt, SO
Lipids in health and disease. 2017;(1):204
Abstract
BACKGROUND Absorption of EPA and DHA from Omega-3-acid ethyl ester (EE) concentrate supplements occurs most efficiently when taken in context of a fatty meal; adequate fat intake is required to release bile salts that emulsify and pancreatic enzymes that digest omega-3-containing lipids in the intestine. Current guidelines recommend reduction in fat intake and therefore there is a need to optimize the absorption of Omega-3 in those consuming low-fat or no-fat meals. To this end, BASF has developed an Absorption Acceleration Technology, a novel self-micro-emulsifying delivery system (SMEDS) formulation of highly concentrated Omega-3-acid EE which enables rapid emulsification and microdroplet formation upon entering the aqueous environment of the gut therefore enhances the absorption. METHODS Two separate single dose, crossover studies were conducted to determine the relative bioavailability of omega-3-acid EE concentrate, either as a novel SMEDS formulation (PRF-021) or as control, in healthy fasted male and female adults at two dose levels (Study 1 "low dose": 630 mg EPA + DHA in PRF-021 vs. 840 mg EPA + DHA in control; Study 2 "high dose": 1680 mg EPA + DHA in PRF-021 vs. 3360 mg EPA + DHA in control). Blood samples were collected immediately before supplementation and at defined time intervals for 48 h. Plasma concentration of total EPA and DHA were determined for pharmacokinetic analysis, area under the curve (AUC) and maximum observed concentration (Cmax) was determined. RESULTS Total EPA plus DHA absorption from SMEDS formulation PRF-021 were 6.4 and 11.5 times higher compared to control in low- and high-dose studies respectively, determined as the ratio of baseline corrected, dose normalized AUC0-24h of PRF-021 over that of control. EPA and DHA individually showed differing levels of enhancement: the AUC0-24h ratio for EPA was 23.8 and 25.7 in low and high dose studies, respectively, and the AUC0-24h ratio for DHA was 3.6 and 5.6 in low and high dose studies, respectively. Cmax was also increased for both EPA and DHA 2.7- to 9.2-fold. CONCLUSION PRF-021 is a novel SMEDS formulation of Omega-3-acid EE demonstrating a marked improvement in absorption of a single dose of EPA and DHA EE under fasted conditions. This allows adequate absorption of Omega-3 from the supplement without the requirement of a high-fat meal.
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No major effects of vitamin D3 (1,25 dihydroxyvitamin D3) on absorption and pharmacokinetics of folic acid and fexofenadine in healthy volunteers.
Kullak-Ublick, GA, Gubler, C, Spanaus, K, Ismair, MG, Claro da Silva, T, Jetter, A
European journal of clinical pharmacology. 2016;(7):797-805
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Abstract
PURPOSE In Caco-2 cells, folate uptake via the proton-coupled folate transporter (PCFT) increases significantly by a 3-day treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Additionally, mRNA content and protein expression of the transporter OATP1A2 were increased up to ninefold with 1,25(OH)2D3. We investigated whether these in vitro findings can be confirmed in humans in vivo. METHODS Ten healthy volunteers (six women) received 5 mg folic acid orally once before and once together with the last intake of a 10-day course of 0.5 μg 1,25(OH)2D3 orally. One hundred twenty milligrams fexofenadine, an OATP1A2 substrate, was taken in 1 day before the first folic acid intake, and again on the ninth day of 1,25(OH)2D3 intake. Duodenal biopsies were taken for transporter mRNA assessments once before and once on the ninth or tenth day of the vitamin D3 course. Serum folic acid and fexofenadine concentrations were quantified with a chemiluminescence immunoassay and LC-MS/MS, respectively. Pharmacokinetics were compared between periods with standard bioequivalence approaches. RESULTS While geometric mean folic acid AUC0-2h, which mainly reflects absorption, was 0.403 and 0.414 mg/L·h before and after the vitamin D3 course (geometric mean ratio (GMR), 1.027; 90 % confidence interval (90 % CI), 0.788-1.340), the geometric mean fexofenadine AUC0-2h was 1.932 and 2.761 mg/L·h, respectively (GMR, 1.429; 90 % CI, 0.890-2.294). PCFT- and OATP1A2-mRNA expressions in duodenal biopsies were essentially unchanged. CONCLUSIONS No significant changes in folic acid and fexofenadine absorption were observed after a 10-day course of 1,25(OH)2D3 in humans in vivo. This study underlines the importance of confirming in vitro findings in vivo in humans.
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Green tea influences intestinal assimilation of lipids in humans: a pilot study.
Lisowska, A, Stawińska-Witoszyńska, B, Bajerska, J, Krzyżanowska, P, Walkowiak, J
European review for medical and pharmacological sciences. 2015;(2):209-14
Abstract
OBJECTIVE Many data show that green tea (GT) consumption has a beneficial effect on human health, including antiinflammatory, antibacterial and anticarcinogenic activities. However, there are no data on the effect of long-term GT intake on lipid assimilation not related to luminal processes. Therefore, in the present study, we aimed to assess the impact of a three-month diet enriched in green tea extract (GTE) on lipid digestion and absorption in obese humans with metabolic syndrome. PATIENTS AND METHODS Eight obese subjects aged 56-65 years, for three months, consumed a daily portion of GTE enriched bread. 13C-labelled mixed triglyceride breath test (13C MTG-BT) was performed twice; once before and once after three months of GTE consumption. Cumulative percentage dose recovery (CPDR) was assumed to reflect digestion and absorption of lipids. RESULTS Energy and macronutrient intake was stable within the period study. No significant changes in basic anthropological parameters (body weight, BMI, WC, WHR), body fat content (expressed as absolute and relative values), as well as of energy expenditure in the course of the study were observed. Significant decrease in lipid digestion and absorption as assessed using the 13C MTG-BT was observed. CPDR was lower after GTE intake (median <1st-3rd quartile>: 20.8% <14.9-25.6> vs. 15.5 <12.3-20.5>; p < 0.009). CONCLUSIONS Long-term diet containing GTE decreases lipid assimilation, but probably without involvement of luminal effects. However, further studies are needed to confirm this hypothesis and to clarify underlying mechanism.
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Initiation and dose optimization for levodopa-carbidopa intestinal gel: Insights from phase 3 clinical trials.
Lew, MF, Slevin, JT, Krüger, R, Martínez Castrillo, JC, Chatamra, K, Dubow, JS, Robieson, WZ, Benesh, JA, Fung, VS
Parkinsonism & related disorders. 2015;(7):742-8
Abstract
BACKGROUND Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces "off" time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy. METHODS Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J. RESULTS In the open-label study, 92% of 354 patients received monotherapy at post-PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post-PEG-J week 4, mean "off" time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1-4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%). CONCLUSION These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.
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Growth hormone enhances fat-free mass and glutamine availability in patients with short-bowel syndrome: an ancillary double-blind, randomized crossover study.
Seguy, D, Darmaun, D, Duhamel, A, Thuillier, F, Cynober, L, Cortot, A, Gottrand, F, Messing, B
The American journal of clinical nutrition. 2014;(3):850-8
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BACKGROUND Benefits of recombinant human growth hormone (rhGH) alone or combined with glutamine in patients with intestinal failure because of short-bowel syndrome remain controversial. OBJECTIVE We explored effects of rhGH on whole-body protein metabolism in patients with short-bowel syndrome with intestinal failure (SBS-IF) to gain insight into its mechanism of action. DESIGN Eight stable hyperphagic patients with severe SBS-IF received, in a double-blind, randomized crossover study, low-dose rhGH (0.05 mg · kg⁻¹ · d⁻¹) and a placebo for two 3-wk periods. Leucine and glutamine kinetics under fasting and fed conditions, fat-free mass (FFM), and serum insulin were determined on the final day of each treatment. RESULTS rhGH increased FFM and nonoxidative leucine disposal (NOLD; an index of protein synthesis) (P < 0.02), whereas FFM and NOLD were correlated in the fed state (r = 0.81, P = 0.015). With rhGH administration, leucine release from protein breakdown (an index of proteolysis) decreased in the fed compared with fasting states (P = 0.012), which was not observed with the placebo. However, the fast-to-fed difference in leucine release from protein breakdown was not significantly different between rhGH and placebo (P = 0.093). With rhGH, the intestinal absorption of leucine and glutamine increased (P = 0.036) and correlated with serum insulin (r = 0.91, P = 0.002). rhGH increased glutamine de novo synthesis (P < 0.02) and plasma concentrations (P < 0.03) in both fasting and fed states. CONCLUSIONS In SBS-IF patients, feeding fails to decrease proteolysis in contrast to what is physiologically observed in healthy subjects. rhGH enhances FFM through the stimulation of protein synthesis and might decrease proteolysis in response to feeding. Improvements in de novo synthesis and intestinal absorption increase glutamine availability over the physiologic range, suggesting that beneficial effects of rhGH in hyperphagic patients might be achieved without glutamine supplementation.
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Effect of vitamin C on the absorption of levothyroxine in patients with hypothyroidism and gastritis.
Jubiz, W, Ramirez, M
The Journal of clinical endocrinology and metabolism. 2014;(6):E1031-4
Abstract
BACKGROUND Malabsorption of l-T4 is a major clinical problem. Changes in gastric pH caused by several medical illnesses are associated with difficulties in the control of patients with hypothyroidism receiving the hormone. Means to correct these alterations would be of clinical value. OBJECTIVES Our objective was to study the effect of vitamin C on the absorption of l-T4 in patients with hypothyroidism and gastritis. DESIGN Thirty-one patients with hypothyroidism, 28 females age 47.5 ± 13.5 (mean ± SD) years and 3 males age 55.7 ± 11.2 years ingested the dose of l-T4 in 120 mL water containing or not containing 500 mg vitamin C in a solution of pH 2.9 ± 0.1 (mean ± SD). Serum concentrations of free T4 and TSH were measured at the end of 3 periods of 2 months each, 2 controls and 1 vitamin C. Serum total T3 was measured in 16 of the patients, before and at the end of the vitamin C period. Serum TSH and free T4 and T3 were measured by a solid-phase, enzyme-labeled chemiluminescent competitive immunoassay All patients had gastrointestinal pathology and were not in good control when taking l-T4 before the study, and 23 had autoimmune thyroiditis or idiopathic hypothyroidism. The median l-T4 dose was 100 μg with an interquartile range of 50 μg. The protocol was reviewed and approved by our institution's ethics committee. Patients were asked to sign a written consent to participate in the study. RESULTS Serum concentrations of TSH, free T4, and T3 improved while on vitamin C. Serum TSH decreased in all patients (control, 11.1 [10.5] μIU/mL, median [interquartile range]), vitamin C 4.2 (3.7) μIU/mL, P = .0001), and it was normalized in 17 patients (54.8%). The average decrease was 69.2%. Serum T4 was higher with vitamin C in 30 of the 31 patients (control, 1.1 [0.3] ng/dL; vitamin C, 1.3 [0.3] ng/dL; P < .0001), and serum T3 increased as well in all 16 patients in whom it was measured (control, 60.5 [16.5] ng/dL; vitamin C, 70 [21] ng/dL; P < .005). CONCLUSIONS In patients with hypothyroidism and gastrointestinal pathology, vitamin C improves the abnormalities in serum free T4, T3, and TSH concentrations. This approach is helpful in the management of these patients.