+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

A new model-independent physiological approach to study hepatic drug clearance and its applications

, : A new model-independent physiological approach to study hepatic drug clearance and its applications. International Journal of Clinical Pharmacology, Therapy, and Toxicology 22(11): 577-590

After entering the liver a drug molecule is removed by two competitive processes: (a) blood flow to carry it away intact from liver and (b) elimination by hepatic enzyme(s). The relative magnitude of the overall force or efficiency of these two processes will statistically decide its probability for elimination, i.e., extraction ratio (E). Blood flow rate is chosen to represent the force due to blood flow, and the force due to hepatic elimination can then be simply calculated in terms of blood flow per unit time. Under linear conditions any changes in either force can be used to predict new E. Binding in blood, permeability across hepatocellular membrane and intrinsic enzyme activity will affect the hepatic elimination force. The approach employed has virtually made no prior assumptions regarding distribution profiles of drug, enzymes, sinusoids and intracellular bindings as well as drug permeability. Bioavailability predictions upon changes in hepatic flow or protein binding are consistent with most reported data. It can explain potential differences in the fate of drug pre-equilibrated or not pre-equilibrated with blood before entering the liver and also that of metabolite performed or not performed in liver. Importance of erythrocytes as potential elimination barriers in hepatic first-pass effect and existence of both transverse and longitudinal (not considered in previous hepatic models) drug concentration gradients in the liver are emphasized. Applications to studies of instantaneous, time-averaged, beta and intrinsic clearances, as well as hepatic transit time and nonlinear kinetics are discussed. The present simple dynamic approach can also successfully predict the quantitative correlation between renal clearance and changes in urine flow and/or pH for many drugs in humans and animals. Using steady-state input conditions the present derived equations can be obtained thus adding the mathematical validity of the approach.


PMID: 6389376

Other references

Tivesten, A.; Mellström, D.; Jutberger, H.; Fagerberg, Börn.; Lernfelt, B.; Orwoll, E.; Karlsson, M.K.; Ljunggren, O.; Ohlsson, C., 2007: Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. Objectives This study sought to determine whether serum levels of testosterone and estradiol associate with lower extremity peripheral arterial disease (PAD) in a large population-based cohort of elderly men.Background Few studies have explored t...

Olmos, Y.; Carlton, J.G., 2016: The ESCRT machinery: new roles at new holes. The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit....

Khalil, K.Fatima.; Saeed, W., 2010: Pulmonary embolism in soldiers serving at high altitude. To determine the frequency of different risk factors for pulmonary embolism with particular reference to high altitude as one of the factors. Cross sectional, analytical study. Department of Pulmonology, Military Hospital Rawalpindi, from December...

Lakomy, M., 1986: Changes in acetylcholinesterase activity of the nerve system of swine ovaries in different periods of lactation. Morphological features of AChE-positive nerves in the ovaries of sows in different periods of lactation, as well as the activity of AChE in these nerves, have been described. For the tests there were used twenty Large White Polish breed primipara...

Kaul C.L.; Talwalker P.K.; Grewal R.S., 1976: Effect of chemical sympathectomy adrenalectomy and adrenergic alpha blocking agents and beta blocking agents on the development of hyper glycemia induced by streptozotocin in the rat. Experientia (Basel) 32(8): 1072-1074

Leonard, M.; Metcalfe, A.V.; Lambert, M.F., 2006: Efficient simulation of a space-time Neyman-Scott rainfall model. Existing space-time Neyman-Scott models characterize rainfall as the arrival of rain cells, clustered in time and independently distributed in space. Each cell is described as a cylinder having a random intensity (height) and random radial coverag...

Carignano Claudio A.; Cioccale Marcela A., 1997: Landscapes antiquity of the central Sierras Pampeanas (Argentina); geomorphic evolution since the Gondwanas times. Supplementi di Geografia Fisica e Dinamica Quaternaria (Testo Stampato) 3, Part 1: 104

Anonymous, 1970: The American Association of Orthodontists. Tic 29(4): 15-15

Curtis J.; Bourne F.J., 1973: Half lives of immuno globulin g immuno globulin a and immuno globulin m in the serum of new born pigs. Immunology 24(1): 147-155

Medalion, B.; Merin, G.; Milgalter, E.; Elami, A.; Borman, J.; Shimon, D.; Deviri, E.; Izhar, U.; Deeb, M.; Shargal, Y.; Grienfeld, G.; Kramer, M.R., 1996: Early experience in lung transplantation. Lung transplantation is becoming an acceptable mode of therapy worldwide for the end-stage lung disease. We present our initial experience with the first 10 consecutive lung transplant patients at Hadassah University Hospital. There were 5 males a...