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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Any drug has several barriers to overcome when administered orally, including being spat out or vomited. It must survive the acidity of the stomach and then the alkaline environment of the small intestine where the majority of drugs are absorbed. Once absorbed through the bowel wall, drugs pass via the portal circulation to the liver where they may undergo first-pass metabolism. Some drugs also undergo first-pass metabolism at the bowel wall. Individuals with low levels of hepatic enzyme activity may have increased bioavailability, due to a lower first pass effect. Co-administration of enzyme inhibitors can have a similar effect. The fraction of drug removed from the blood as it passes through the liver is known as the extraction ratio.
Cardiovascular Medications in Pregnancy
Published in Afshan B. Hameed, Diana S. Wolfe, Cardio-Obstetrics, 2020
Hepatic extraction ratio refers to the fraction of drug removed from the circulation by the liver. Some drugs like propranolol, verapamil, and nitroglycerin are rapidly taken up into hepatocytes, and their clearance depends on the rate of blood flow to the liver. In pregnancy, perfusion to the liver stays stable or increases, causing some drugs to be metabolized faster, which in turn may require an increase in drug dosing. Clearance of those drugs that are not affected by hepatic clearance, such as warfarin, depends on the intrinsic hepatic activity as well as on the unbound fraction of the drug in plasma [12].
Psychopharmacology EMIs
Published in Michael Reilly, Bangaru Raju, Extended Matching Items for the MRCPsych Part 1, 2018
Extraction ratio for a drug by a specific organ.First-order kinetics.Total clearance.Zero-order kinetics.
Drug metabolic stability in early drug discovery to develop potential lead compounds
Published in Drug Metabolism Reviews, 2021
Siva Nageswara Rao Gajula, Nimisha Nadimpalli, Rajesh Sonti
A clear idea about in vivo clearance values should be obtained to understand the in vitro system's clearance scales. For conversion of mL/min/70 Kg to µL/min/mg units, an approximation that 70 Kg human contains 1800 g of the liver in which 40 mg of microsomal protein per one gram of liver (Hakooz et al. 2006) or 99 × 106 hepatic cells is considered (Barter et al. 2007). Also, an assumption of a fraction unbound value of 1 and an extraction ratio (the fraction of drug that is eliminated from the blood by an organ) of 0.3 and 0.7 for the low and high boundaries, respectively, is used as defined by Wilkinson and Shand (1975). Thus, drugs with HLM CLint values of ≥47, 8.6–47, and ≤ 8.6 µL/min/mg protein are categorized as high, medium, and low clearance drugs. Similarly, hepatocyte CLint values of ≥28, 5.1–28, and ≤ 5.1 µL/min/106 cells are classified as high, medium, and low clearance drugs, respectively.
Plasma protein binding, metabolism, reaction phenotyping and toxicokinetic studies of fenarimol after oral and intravenous administration in rats
Published in Xenobiotica, 2021
Kajal Karsauliya, Ashish Kumar Sonker, Manisha Bhateria, Isha Taneja, Anshuman Srivastava, Manu Sharma, Sheelendra Pratap Singh
In vitro metabolic stability of FNL was determined using liver microsomes of rats and humans to subsequently assess the in vivo clearance. It was observed that at the end of the incubation period (45 min), around 47% and 28% of FNL remained unmetabolized in rat and human liver microsomes, respectively (Figure 3). Using the slope of the depletion profile, in vitro t1/2 of FNL was found to be 43.09 min and 25.54 min, respectively, for rat and human liver microsomes. Further, intrinsic clearance (CLint) and hepatic intrinsic clearance (CLint hepatic) values were sought (using Equations (2) & (3)) and computed to be 0.032 mL/min/mg protein and 77.19 mL/min/kg, respectively, for rat liver microsomes and 0.054 mL/min/mg protein and 51.27 mL/min/kg, respectively, for human liver microsomes. Consequently, CLint hepatic values were scaled using a well-stirred model to estimate in vivo hepatic clearance (CLhepatic) of FNL in rats and humans, and the values were recorded to be 36.71 mL/min/kg and 14.39 mL/min/kg, respectively. The extraction ratio (ER) was found to be 0.52 for rats and 0.72 for humans, respectively.
Continuous extracorporeal clearance in metformin-associated lactic acidosis and metformin-induced lactic acidosis: a systematic review
Published in Clinical Toxicology, 2022
Matthew S. Correia, B. Zane Horowitz
It is unclear if the extraction ratio is toxokinetically or even clinically relevant. Not only was metformin previously noted to only be moderately dialyzable by EXTRIP, but high-quality data by Mujtaba and colleagues [59] indicated that metformin elimination approached 80–89% of urea clearance, and 83–90% of creatinine clearance. And in this study, even though both the lower and upper bounds of the extraction ratio range (6.3% and 48.9%) were reported in the same patient encounter, the corresponding clearance rates during these time frames were similar, 22.3 mL/min and 26.1 mL/min, respectively.