Necessary modification of formulae estimating the reabsorption rate for drugs subject to enterohepatic recirculation

1991 ◽  
Vol 19 (4) ◽  
pp. 469-472 ◽  
Author(s):  
Masahiro Kurita
Keyword(s):  
Enterohepatic Recirculation ◽  
Reabsorption Rate

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

Resveratrol: nanocarrier-based delivery systems to enhance its therapeutic potential

Nanomedicine ◽  
2020 ◽  
Author(s):  
Gurinder Singh
Keyword(s):  
Water Solubility ◽  
Therapeutic Potential ◽  
Hepatic Metabolism ◽  
Enterohepatic Recirculation ◽  
Systemic Delivery ◽  
First Pass ◽  
High Doses ◽  
Sites Of Action

Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic compound existing in trees, peanuts and grapes and exhibits a broad spectrum of promising therapeutic activities, but it is unclear whether this entity targets the sites of action after oral administration. In vivo applicability of resveratrol has limited success so far, mainly due to its incompetent systemic delivery resulting from its low water solubility, poor bioavailability and short biological half-life. First-pass metabolism and presence of enterohepatic recirculation create doubt on the biological application of high doses typically used for in vitro trials. To augment bioavailability, absorption and uptake of resveratrol by cellular internalization, countless approaches have been implemented which involve the use of nanocarriers. Nanocarriers are a well-known delivery system used to reduce first-pass hepatic metabolism, overcome enterohepatic recirculation and accelerate the absorption of drugs via lymphatic pathways.

scholarly journals Possible Mechanism by Which the Carbapenem Antibiotic Panipenem Decreases the Concentration of Valproic Acid in Plasma in Rats

1998 ◽  
Vol 42 (12) ◽  
pp. 3136-3140 ◽  
Author(s):  
Saori Kojima ◽  
Masayuki Nadai ◽  
Kiyoyuki Kitaichi ◽  
Li Wang ◽  
Toshitaka Nabeshima ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Body Weight ◽  
Bile Duct ◽  
Plasma Concentrations ◽  
Enteric Bacteria ◽  
Enterohepatic Recirculation ◽  
Constant Infusion ◽  
Initial Space ◽  
Induced Changes ◽  
Carbapenem Antibiotic

ABSTRACT There is evidence indicating that the carbapenem antibiotic panipenem decreases plasma concentrations of valproic acid (VPA) in epileptic patients during VPA therapy. The mechanism for panipenem-induced changes in the pharmacokinetics of VPA was investigated in rats with and without bile duct cannulation. The effect of panipenem on the pharmacokinetics of diclofenac, which undergoes extensive enterohepatic recirculation, was also examined. VPA (50 mg/kg of body weight) or diclofenac (10 mg/kg of body weight) was administered intravenously under the steady-state plasma panipenem concentration of 4 μg/ml, which had been achieved by a constant infusion rate. Panipenem decreased the plasma VPA concentrations in rats without bile duct cannulation but did not change the volume of the initial space and protein binding of VPA. However, panipenem had no effect on the plasma VPA concentrations and the biliary excretion of VPA in rats with bile duct cannulation. The secondary increase in plasma diclofenac concentration observed in the absence of panipenem was diminished in the presence of panipenem. These findings suggest that panipenem decreases plasma VPA concentrations by suppressing its enterohepatic recirculation, probably due to a panipenem-induced decrease in the numbers of enteric bacteria.

Effect of Temperature on Sodium Reabsorption in the Perfused Bullfrog Kidney

1956 ◽  
Vol 185 (3) ◽  
pp. 545-548 ◽  
Author(s):  
T. Hoshiko
Keyword(s):  
Activation Energy ◽  
Active Transport ◽  
Sodium Concentration ◽  
Effect Of Temperature ◽  
Sodium Reabsorption ◽  
Arrhenius Activation Energy ◽  
Urine Sodium ◽  
Diffusion Limited ◽  
Filtered Load ◽  
Reabsorption Rate

The bullfrog kidney was perfused with a PVP-Conway fluid at constant temperatures ranging from 6–27°C. At the higher temperatures the urine sodium concentration was initially low and rose rapidly, while at the lower temperatures, the urinary sodium started high and rose less steeply. The logarithm of the calculated net sodium reabsorption rate fell linearly with time, independently of changes in filtered load. At the higher temperatures the initial sodium reabsorption rate was higher but fell more rapidly than at the lower temperatures. The initial values for sodium reabsorption were used to calculate the Arrhenius activation energy, which was found to be approximately 29 Cal/m. The exponential fall in sodium reabsorption was interpreted in terms of a carrier diffusion limited system as the mechanism of active transport.

Flash photolysis of caged nitric oxide inhibits proximal tubular fluid reabsorption in free-flow nephron

2005 ◽  
Vol 289 (2) ◽  
pp. R620-R626 ◽  
Author(s):  
Kay-Pong Yip
Keyword(s):  
Nitric Oxide ◽  
Proximal Tubule ◽  
Flash Photolysis ◽  
Tubular Reabsorption ◽  
Fluid Reabsorption ◽  
Proximal Tubular ◽  
Tubular Flow ◽  
Tubular Fluid Reabsorption ◽  
Reabsorption Rate ◽  
Proximal Tubular Reabsorption

A nonobstructing optical method was developed to measure proximal tubular fluid reabsorption in rat nephron at 0.25 Hz. The effects of uncaging luminal nitric oxide (NO) on proximal tubular reabsorption were investigated with this method. Proximal fluid reabsorption rate was calculated as the difference of tubular flow measured simultaneously at two locations (0.8–1.8 mm apart) along a convoluted proximal tubule. Tubular flow was estimated on the basis of the propagating velocity of fluorescent dextran pulses in the lumen. Changes in local tubular flow induced by intratubular perfusion were detected simultaneously along the proximal tubule, indicating that local tubular flow can be monitored in multiple sites along a tubule. The estimated tubular reabsorption rate was 5.52 ± 0.38 nl·min−1·mm−1 ( n = 20). Flash photolysis of luminal caged NO (potassium nitrosylpentachlororuthenate) was induced with a 30-Hz UV nitrogen-pulsed laser. Release of NO from caged NO into the proximal tubule was confirmed by monitoring intracellular NO concentration using a cell-permeant NO-sensitive fluorescent dye (DAF-FM). Emission of DAF-FM was proportional to the number of laser pulses used for uncaging. Photolysis of luminal caged NO induced a dose-dependent inhibition of proximal tubular reabsorption without activating tubuloglomerular feedback, whereas uncaging of intracellular cGMP in the proximal tubule decreased tubular flow. Coupling of this novel method to measure reabsorption with photolysis of caged signaling molecules provides a new paradigm to study tubular reabsorption with ambient tubular flow.

Glomerular Filtration Rate and Segmental Tubular Function in the Early Phase after Transplantation/Uninephrectomy in Recipients and Their Living-Related Kidney Donors

1994 ◽  
Vol 87 (5) ◽  
pp. 519-523 ◽  
Author(s):  
Anne-Lise Kamper ◽  
Niels-Henrik Holstein-Rathlou ◽  
Svend Strandgaard ◽  
Paul Peter Leyssac ◽  
Ole Munck
Keyword(s):  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Sodium Reabsorption ◽  
Lithium Clearance ◽  
Kidney Donors ◽  
Fluid Reabsorption ◽  
Living Related ◽  
Reabsorption Rate ◽  
Sodium Clearance

1. Glomerular filtration rate and sequential tubular function were investigated in 18 adult renal transplant recipients and in their matched, adult living-related kidney donors before and 5 days after transplantation/uninephrectomy. At day 54, 13 donors and 11 recipients were re-investigated. Sixteen of these constituted eight matched pairs. This reduction in the study population was caused by the application of two withdrawal criteria. 2. In the recipients glomerular filtration rate was unchanged at day 5 and had increased to 61 ml/min at day 54 (P < 0.05). In the donors glomerular filtration rate had increased to 59 ml/min by day 5 (P < 0.01) and was unchanged at day 54. 3. In the recipients lithium clearance was unchanged at day 5 and had increased to 23 ml/min at day 54 (P < 0.01). In the donors the lithium clearance had increased by day 5 (P < 0.01). 4. In the recipients the absolute proximal fluid reabsorption rate was about 36 ml/min throughout the study period. In the donors the absolute proximal fluid reabsorption rate had increased to 42 ml/min by day 5 (P < 0.05) and increased further to 44 ml/min by day 54 (P < 0.01). 5. In the recipients sodium clearance increased from 0.54 ml/min to 2.10 ml/min at day 54 (P < 0.01). In the donors it increased from 0.64 ml/min to 0.99 ml/min at day 54 (P < 0.05). 6. Donor-recipient comparison showed that at day 54 there was no significant difference with regard to glomerular filtration rate, lithium clearance, absolute and fractional proximal fluid reabsorption rate and absolute distal sodium reabsorption rate. The sodium clearance was higher and the fractional distal sodium reabsorption rate was lower in the recipients. 7. In conclusion, the difference in function between donors and recipients at day 5 can probably be explained by the damaging effect of many inevitable factors on the graft. Fifty-four days after transplantation the function of the graft could not be distinguished from that of the remaining kidney. This suggests that the ideal homograft possesses a normal potential for compensatory hypertrophy once the effects of the initial post-operative ischaemia and toxic factors have subsided.

Effects of verapamil alone and with captopril on blood pressure and bilateral renal function in Goldblatt hypertensive rats

1986 ◽  
Vol 70 (5) ◽  
pp. 453-460 ◽  
Author(s):  
Wann-Chu Huang
Keyword(s):  
Renal Function ◽  
Arterial Pressure ◽  
Free Water ◽  
Hypertensive Rats ◽  
Hypotensive Action ◽  
Excretory Function ◽  
Change Function ◽  
Distal Tubules ◽  
And Control ◽  
Reabsorption Rate

1. The effects of verapamil infusion alone and superimposed with captopril on arterial pressure and bilateral renal function were evaluated in 21 two-kidney, one-clip Goldblatt hypertensive rats and in 13 control rats. 2. Verapamil significantly decreased arterial pressure of both hypertensive and control rats. Addition of captopril further reduced arterial pressure in hypertensive rats only. 3. There were significant increases in glomerular filtration rate (GFR), urine flow and absolute and fractional excretory rates of sodium and potassium in the non-clipped kidney. In contrast, these renal indices decreased in the clipped kidney. Superimposed captopril during verapamil infusion did not significantly change function of the non-clipped kidney but further depressed function of the clipped kidney. 4. In control rats, no significant change in GFR occurred in response to drugs. Renal excretion of water and sodium, but not potassium, increased after verapamil. However, the diuresis and natriuresis were less pronounced than those seen in the non-clipped kidney of hypertensive rats. 5. There was a proportionate increase in osmolar clearance and free water reabsorption rate in the non-clipped kidney and the normal kidney. The linear relationship did not change after verapamil infusion. 6. The results suggest that verapamil enhances the excretory function of the non-clipped kidney of Goldblatt hypertensive rats via increased GFR and decreased tubular reabsorption in the proximal and/or distal tubules despite its hypotensive action.

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