Clearance biliary

Sasaki M, Suzuki H, Aoki J, Ito K, Meier PJ and Sugiyama Y. Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Mol Pharmacol 2004 66 450-9. 

Inorganic lead ions are not known to be metabolized in the body but they are complexed by macromolecules. Lead that is not retained in the body is excreted principally by the kidney as salts or through biliary clearance into the gastrointestinal tract in the form of organometallic conjugates. 

This model integrates existing in vitro data, such as Caco-2 permeability (Papp) and metabolic stability in liver S9 or microsomes, to estimate bioavailability as being either low, medium, or high. Oral bioavailability predictions for not only humans but also other species can be made by using the metabolic stability values of drugs in liver microsomal enzyme preparations from that species. A premise of this model is that metabolic clearance is more important than renal or biliary clearance in determining bioavailability. However, despite the lack of in vitro renal... 

Oral bioavailability of a drug is primarily dependent upon its rate and extent of drug absorption and systemic clearance. Systemic clearance is primarily composed of hepatic, renal and biliary clearance. The PK properties are in turn directly impacted by the drug s physical properties, such as, log P, log D and pKa. The physical properties are in turn a function of the compound s structure, molecular weight, number of hydrogen bond donors and acceptors, and number of rotatable bonds. Oral bioavailability is the outcome from the dynamic interplay of these factors in the biological system. 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

O. 69 LVh/kg renal and biliary clearance of unchanged drug each contribute approximately 5%. About 30% of the dose is excreted in the feces 53% of the oral dose is excreted in the urine, primarily as metabolites. Of the five metabolites that have been identified, 25-0-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite parent ADC ratio of 0.1 and 0.07, respectively. The 25-0-desacetyl metabolite has an activity equal to the parent drug and contributes less than or equal to 10% to the total antimicrobial activity. 

Nafcillin, oxacillin Intravenous, added stability to staphylococcal 5 lactamase, biliary clearance... 

Indomethacin, introduced in 1963, is an indole derivative (Figure 36-1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Probenecid prolongs indomethacin s half-life by inhibiting both renal and biliary clearance. 

As glomerular filtration has an approximate molecular size limit of 20-30 kDa, mAbs do not undergo filtration in the kidneys due to their relatively large size. The situation is different, however, for low molecular-mass antibody fragments, which can be filtered. Tubular secretion has not been reported to occur to any significant extent for mAbs, and peptides/small proteins are readily reabsorbed in the proximal or distal tubule of the nephron (potentially also mediated by the neonatal Fc receptor, Fc-Rn), or are even metabolized. Thus, renal elimination in total is uncommon or low for mAbs. Biliary excretion of mAbs has been reported only for IgA molecules, and only to a very small extent. Therefore, total clearance (CL) does usually not comprise renal or biliary clearance. 

Figure 6 Directional transport of pravastatin in Oatplb2/Mrp2 double transfectants in the apical direction (A), and comparison of in vivo biliary excretion clearance and in vitro transcellular transport clearance across the double transfectant (B). (A) Transcellular transport across the monolayers of MDCK II cells was determined in the basal-to-apical and the opposite direction. (B) The x axis represents CLint determined in vitro multiplied by /B and the scaling factor, and the y axis represents the in vivo biliary clearance defined for the blood ligand concentrations. The symbol ( ) represents data whose x axis values were corrected for the scaling factor (a = 17.9). The solid line represents the theoretical curve, and the symbol (o), the observed data. Source From Ref. 59.

All orally administered chugs must pass through the gastrointestinal tract to reach the blood and thus pass the barrier formed by the enterocytes in the intestine. For years, low first-pass bioavailability of a drug was attributed mainly to clearance via hepatic metabolism and biliary clearance or incomplete absorption in the intestine due to poor solubility or intrinsic permeability properties. Although these are important factors in determining the overall oral bioavailability of certain... 

Angelin B, Arvidsson A, Dahlqvist R, et al. Quinidine reduces biliary clearance of digoxin in man. Eur J Clin Invest 1987 17(3) 262-265. 

Another sinusoidal transporter catalyzes Na+-independent uptake of organic anions and is instrumental for biliary clearance of glucuronidated and sulfated steroids, the diagnostic chemical bromosulfophthalein (BSP) and possibly bilirubin. Canalicular transport of glucuronidate and GSH conjugates is coupled to ATP... 

Studies in animals have demonstrated that biliary clearance actually may exceed plasma clearance for some drugs and in species with extensive enterohepatic circulation (9). Interruption of enterohepatic... 

Interactions with indometacin have been documented through inhibition of renal tubular excretion (26,27). In 17 patients with rheumatoid arthritis, probenecid 500 mg bd improved the therapeutic response to indometacin 25 mg tds over 3 weeks (28). There were changes in the pharmacokinetics of indometacin, which the authors attributed to a reduction in the non-renal clearance of indome-tacin, possibly because of reduced biliary clearance. 

Because of the importance of hepatic metabolism in SN-38 elimination by glucuronidation, the biliary clearance of irinotecan and its metabolites is delayed in patients with impaired hepatic function (55-57), and there is a negative correlation between serum bilirubin concentrations and the total body clearance of irinotecan. In a patient with moderately impaired liver function, it was necessary to reduce the dose to 100 mg/m instead of 350 mg/m intravenously thrice-weekly, in order to achieve half-lives and C ax values of irinotecan and SN-38 comparable to those observed in patients with normal liver function (55). However, the corresponding AUCs were still significantly increased, resulting in more severe leukopenia and delayed diarrhea. The authors concluded that to improve tolerance, exposure to the drug in a patient of this kind should not exceed 30 mg/m intravenously. 

Abe K, Bridges AS, Brouwer KL. Use of sandwich-cultured human hepatocytes to predict biliary clearance of angiotensin II receptor blockers and HMG-CoA reductase inhibitors. Drug Metab Dispos. 2009 37(3) 447-452. 

Dietary lead that is not absorbed in the gastrointestinal tract is excreted in the feces. Lead that is not distributed to other tissues is excreted through the kidney and, to a lesser extent, by biliary clearance (WHO, 2000). 

Figure 11.5 Vectorial transcellular transport of pravastatin, its basal-to-apical transcellular drugs in double-transfected cells, (a) The double- transport is significantly higher compared to the transfected cells expressing OATP1B1 (uptake apical-to-basal transport [177]. (b) Prediction of transporter) on the basal side and MRP2 (efflux in vivo biliary clearance of several bisubstrates of transporter) on the apical side have been rat Oatplb2 and Mrp2 from their in vitro...

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