Pharmacokinetic Analysis of Ramatroban Using a Recirculatory Model with Enterohepatic Circulation by Measuring Portal and Systemic Blood Concentration Difference in Sprague-Dawley and Eisai Hyperbilirubinemic Rats

ABSTRACT The liver is crucial to pharmacology, yet substantial knowledge gaps exist in the understanding of its basic pharmacologic processes. An improved understanding for humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats by using samples collected by fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical resection. Thirteen Sprague-Dawley rats were evaluated, nine of which received paritaprevir/ritonavir at 30/20 mg/kg of body weight by oral gavage daily for 4 or 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3, or 5 passes (FNA1, FNA3, and FNA5); via CNB (16G needle); and via surgical resection. Drug concentrations in plasma were also assessed. Analyses included noncompartmental pharmacokinetic analysis and use of Bland-Altman techniques. All liver tissue samples had higher paritaprevir and ritonavir concentrations than those in plasma. Resected samples, considered the benchmark measure, resulted in estimations of the highest values for the pharmacokinetic parameters of exposure (maximum concentration of drug in serum [C max] and area under the concentration-time curve from 0 to 24 h [AUC0–24]) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between tissue resection and CNB, with 15% bias, followed by FNA3 and FNA5, with 18% bias, and FNA1 and FNA3, with a 22% bias for paritaprevir. Paritaprevir and ritonavir are highly concentrated in rat liver. Further research is needed to validate FNA sampling for humans, with the possible derivation and application of correction factors for drug concentration measurements.

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Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog NSC 655649 Given Daily for Five Consecutive Days

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.8.2309 ◽

2001 ◽

Vol 19 (8) ◽

pp. 2309-2318 ◽

Cited By ~ 23

Author(s):

Afshin Dowlati ◽

Charles L. Hoppel ◽

Stephen T. Ingalls ◽

Susan Majka ◽

Xiaolin Li ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

Enterohepatic Circulation ◽

Central Venous Access ◽

Area Under The Curve ◽

Venous Access ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Analysis ◽

High Concentration ◽

Minor Response

PURPOSE: Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated dose (MTD) of rebeccamycin analog when given on a daily × 5 schedule repeated every 3 weeks, characterize the toxicity profile using this schedule, observe patients for antitumor response, and determine the pharmacokinetics of the agent and pharmacodynamic interactions. PATIENTS AND METHODS: Thirty assessable patients received a total of 153 cycles according to the following dose escalation schema: 60, 80, 106, 141, and 188 mg/m2/d × 5 days. RESULTS: Grade 2 phlebitis occurred in all patients before the use of central venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m2/d × 5 days in both previously treated and chemotherapy-naive patients. Pharmacokinetic analysis revealed a three-compartmental model of drug elimination and a long terminal half-life (154 ± 55 hours). The percentage drop in absolute neutrophil count correlates with the area under the curve∞. The presence of a second peak during the elimination phase as well as a high concentration of NSC 655649 in biliary fluid compared with the corresponding plasma measurement (one patient) is suggestive of enterohepatic circulation. Two partial responses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer and one patient with cholangiocarcinoma experienced either a minor response or a significant period of freedom from progression. CONCLUSION: The recommended phase II dose for NSC 665649 on a daily × 5 every 3 weeks schedule is 141 and 165 mg/m2/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.

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Anesthesia and microvascular dynamics in spontaneously hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1981.241.6.h821 ◽

1981 ◽

Vol 241 (6) ◽

pp. H821-H828

Author(s):

F. A. De Lano ◽

B. W. Zweifach

Keyword(s):

Blood Pressure ◽

Systemic Blood Pressure ◽

Vessel Diameter ◽

Background Information ◽

Unstable State ◽

Sprague Dawley ◽

Systemic Blood ◽

Spontaneously Hypertensive ◽

Anesthetic Agents ◽

Wistar Kyoto

Studies on pressure dynamics in rats under local anesthesia were carried out to provide background information for subsequent intravital analysis of microvascular behavior in a skeletal muscle. An alpha-chloralose-urethan mixture (1:13.3%) was selected as the general anesthesia having the least effect on systemic pressures in spontaneous hypertensive (SHR) as well as normotensive (WKY), Sprague-Dawley and Wistar-Kyoto rats. Anesthetic agents, in general, lower systemic blood pressure in SHR by 30—50 mmHg and thereby distort microcirculatory flow and blood vessel-diameter relationships. Insertion of a plastic catheter into the trachea of the anesthetized rat, to maintain an open airway, had a complex effect on heart rate and systemic blood pressure and left the pressure in an unstable state. Severity of the change depended on the age of the rat and the anesthetic agent; hypertensive animals were especially vulnerable.

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Effect of fasting on the enterohepatic circulation of bile acids in rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1994.267.5.g836 ◽

1994 ◽

Vol 267 (5) ◽

pp. G836-G842 ◽

Cited By ~ 2

Author(s):

R. Dumaswala ◽

D. Berkowitz ◽

K. D. Setchell ◽

J. E. Heubi

Keyword(s):

Bile Salt ◽

Bile Acids ◽

Fluorescence Anisotropy ◽

Enterohepatic Circulation ◽

Basolateral Membrane ◽

Sprague Dawley ◽

Transport Velocity ◽

Phospholipid Ratio ◽

Menten Constant ◽

Fasted Rats

Fasting Sprague-Dawley rats for 72 h resulted in inhibition of bile salt synthesis, reduced bile flow and bile salt secretion rate, and reduced duodenal and portal venous bile acid concentrations. The initial rate of ileal brush border membrane (BBM) taurocholate (TC) uptake was markedly reduced in the fasted group (45% of control). TC uptake by BBM was saturable, with similar maximal transport velocity for the fasted rats and controls (1.69 +/- 0.06 and 1.62 +/- 0.017 nmol.mg protein-1.min-1, respectively) but higher Michaelis-Menten constant for fasted rats than for controls (96.9 +/- 20.0 and 54.9 +/- 10.2 microM, respectively). Hepatic basolateral membrane (BLM) TC uptake was enhanced by 65% in fasted animals. Transport kinetics in BLM had a similar Michaelis-Menten constant for fasted rats and controls (31.6 +/- 8.2 and 27.3 +/- 4.7 microM, respectively), and maximal transport velocity was higher for fasted rats than for controls (1.84 +/- 0.017 and 1.11 +/- 0.014 nmol.mg protein-1.min-1). The cholesterol-to-phospholipid ratio and fluorescence anisotropy in BLM of fasted rats decreased, and the cholesterol-to-phospholipid ratio and fluorescence anisotropy increased in ileal BBM. Alterations in the enterohepatic circulation of bile acids with fasting may alter expression of transport proteins for bile salts by direct effects on synthesis or indirectly through membrane lipid compositional changes.

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In vivo metabolic tracking of 14C-radiolabelled isoflavones in kudzu (Pueraria lobata) and red clover (Trifolium pratense) extracts

British Journal Of Nutrition ◽

10.1017/s000711450999047x ◽

2009 ◽

Vol 102 (10) ◽

pp. 1523-1530 ◽

Cited By ~ 8

Author(s):

Jonathan G. Mun ◽

Michael D. Grannan ◽

Pamela J. Lachcik ◽

Adam Reppert ◽

Gad G. Yousef ◽

...

Keyword(s):

Trifolium Pratense ◽

Enterohepatic Circulation ◽

Red Clover ◽

Root Culture ◽

Biochanin A ◽

Blood Collection ◽

Pueraria Lobata ◽

Sprague Dawley ◽

Sprague Dawley Rats

Absorption, distribution and elimination of 14C-labelled isoflavone-containing extracts from kudzu (Pueraria lobata) root culture and red clover (Trifolium pratense) cell culture were investigated in an in vivo rat model. The predominant isoflavones in the kudzu extract were the glycosides puerarin, daidzin and malonyl daidzin, while in the red clover extract, the major isoflavones were formononetin and its derivatives, genistein and biochanin A, with radioactivities of 3·770 and 7·256 MBq/g, respectively. Male Sprague–Dawley rats, implanted with a jugular catheter and a subcutaneous ultrafiltrate probe, were orally administered with 14C-labelled isoflavone extracts from either kudzu or clover cell cultures. Serum, interstitial fluid (ISF), urine and faeces were collected using a Culex® Automated Blood Collection System for 24 h. Analysis of bone tissues revealed that radiolabel accumulated in the femur, tibia and vertebrae at 0·04, 0·03 and 0·01 % of the administered dose, respectively, in both kudzu and red clover treatments. The liver accumulated the greatest concentration of radiolabel among the tissues tested, at 1·99 and 1·54 % of the administered kudzu and red clover extracts, respectively. Serum and ISF analysis showed that both extracts were rapidly absorbed, distributed in various tissues, and largely eliminated in the urine and faeces. Urine and faeces contained 8·53 and 9·06 % of the kudzu dose, respectively, and 3·60 and 5·64 % of the red clover dose, respectively. Serum pharmacokinetics suggest that extracts from kudzu may undergo enterohepatic circulation.

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Safety Evaluation of Lipid Nanoparticle–Formulated Modified mRNA in the Sprague-Dawley Rat and Cynomolgus Monkey

Veterinary Pathology ◽

10.1177/0300985817738095 ◽

2017 ◽

Vol 55 (2) ◽

pp. 341-354 ◽

Cited By ~ 29

Author(s):

Maja Sedic ◽

Joseph J. Senn ◽

Andy Lynn ◽

Michael Laska ◽

Mike Smith ◽

...

Keyword(s):

Blood Cell ◽

Intravenous Infusion ◽

Cell Mass ◽

Pharmacokinetic Analysis ◽

High Dose ◽

Sprague Dawley ◽

Test Species ◽

Cell Counts ◽

Pharmacologically Active

The pharmacology, pharmacokinetics, and safety of modified mRNA formulated in lipid nanoparticles (LNPs) were evaluated after repeat intravenous infusion to rats and monkeys. In both species, modified mRNA encoding the protein for human erythropoietin (hEPO) had predictable and consistent pharmacologic and toxicologic effects. Pharmacokinetic analysis conducted following the first dose showed that measured hEPO levels were maximal at 6 hours after the end of intravenous infusion and in excess of 100-fold the anticipated efficacious exposure (17.6 ng/ml) at the highest dose tested.24 hEPO was pharmacologically active in both the rat and the monkey, as indicated by a significant increase in red blood cell mass parameters. The primary safety-related findings were caused by the exaggerated pharmacology of hEPO and included increased hematopoiesis in the liver, spleen, and bone marrow (rats) and minimal hemorrhage in the heart (monkeys). Additional primary safety-related findings in the rat included mildly increased white blood cell counts, changes in the coagulation parameters at all doses, as well as liver injury and release of interferon γ–inducible protein 10 in high-dose groups only. In the monkey, as seen with the parenteral administration of cationic LNPs, splenic necrosis and lymphocyte depletion were observed, accompanied with mild and reversible complement activation. These findings defined a well-tolerated dose level above the anticipated efficacious dose. Overall, these combined studies indicate that LNP-formulated modified mRNA can be administered by intravenous infusion in 2 toxicologically relevant test species and generate supratherapeutic levels of protein (hEPO) in vivo.

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Determinants of maximal oxygen uptake in rats acclimated to simulated altitude

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.4.1608 ◽

1993 ◽

Vol 75 (4) ◽

pp. 1608-1614 ◽

Cited By ~ 28

Author(s):

N. C. Gonzalez ◽

R. L. Clancy ◽

P. D. Wagner

Keyword(s):

Barometric Pressure ◽

Maximal Heart Rate ◽

Sprague Dawley ◽

Concentration Difference ◽

Arterial Blood ◽

Sprague Dawley Rats ◽

Significant Difference ◽

Maximal Cardiac Output ◽

O2 Concentration ◽

Hypoxic Exercise

The effect of acclimation to hypoxia on maximal O2 uptake (VO2max), maximal cardiac output (Qmax), and arteriovenous O2 concentration difference (a-vCO2) was studied in male Sprague-Dawley rats acclimated for 3 wk to a barometric pressure of approximately 380 Torr (A rats). Nonacclimated control animals were pair-fed littermates maintained at an ambient barometric pressure of approximately 740 Torr (NA rats). Both A and NA rats exercised maximally on a treadmill with inspired PO2 maintained at either approximately 72 or 145 Torr. Arterial blood O2 concentration was significantly higher in A than in NA rats (16.0 +/- 0.6 vs. 12.4 +/- 0.3 ml/dl in hypoxia and 28.4 +/- 1.5 vs. 20.1 +/- 0.9 ml/dl in normoxia, respectively; both P < 0.05). During hypoxic exercise VO2max was slightly but significantly higher in A than in NA subjects (55.3 +/- 1.3 vs. 48.8 +/- 1.1 ml STPD.min-1 x kg-1; P < 0.05). In hypoxia a-vCO2 was 16.6 +/- 0.6 and 12.4 +/- 0.4 ml/dl and Qmax was 401 +/- 17 and 489 +/- 9 ml.min-1 x kg-1 in A and NA subjects, respectively (both P < 0.05). A rats showed both lower maximal heart rate and lower maximal stroke volume during hypoxic exercise. In normoxia there was no significant difference in VO2max between A and NA rats (71.8 +/- 2.7 vs. 73.9 +/- 3.1 ml.min-1 x kg-1). As with hypoxia, in normoxia a-vCO2 was significantly higher and Qmax was significantly lower in A than in NA animals.(ABSTRACT TRUNCATED AT 250 WORDS)

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