Biliary excretion clearance

It is also important to predict the in vivo biliary excretion clearance in humans, and for this purpose MDCK II cell lines expressing both uptake and efflux transporters may be used (Fig. 12.3) [92, 93]. It has been shown that MRP2 is expressed on the apical membrane, whereas OATP2 and 8 are expressed on the basolateral membrane after cDNA transfection (Fig. 12.3) [92, 93]. The transcellular transport across such double-transfected cells may correspond to the excretion of ligands from blood into bile across hepatocytes. Indeed, the vectorial transport from the basal to apical side was observed for pravastatin only in OATP2- and MRP2-expressing... 

Aoki, J., Suzuki, H., Sugiyama, Y., Quantitative prediction of in vivo biliary excretion clearance across the bile canalicular membrane from in vitro transport studies with isolated membrane vesicles. Abstract of Millennial World Congress of pharmaceutical Sciences, San Francisco, April 16-20, 2000, p. 92. 

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.

Palmer 1989 Robinson et al.1983). However, the ratio was almost certainly affected by initial chelation with Ca-DPTA, followed by daily intravenous therapy with the chelating agent, Zn-DPTA, treatments that would have increased the urinary excretion of americium (Breitenstein and Palmer 1989). The above not withstanding, the observations made on this subject demonstrate that fecal excretion was an important pathway of excretion in this subject long after mechanical clearance of americium from the respiratory tract would have been complete. This is consistent with observations made in nonhuman primates that show that americium is excreted into bile (see Section 3.4.4.4). However, the extent to which the biliary excretion pathway in humans might resemble that of nonhuman primates is not known. 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

PCP clearance was essentially metabolic, with only 5.3% unchanged by the kidney. About 60% of the dose was recovered in urine mainly as conjugated PCP and conjugated tetraclorohydroquinone. For both routes of administration, about 10% of the dose was recovered in feces as PCP and its metabolites, which indicates that biliary excretion contributes to total elimination (Reigner et al. 1991)... 

The organs of extraction are generally the liver (hepatic clearance - metabolism and biliary excretion CIh) and the kidney (renal excretion, CIr) and the values can be summed together to give an overall value for systemic clearance (Cls) ... 

As observed in Figure 9.4 the intrinsic clearance (as represented by oral unbound clearance CIqu) of UK-147,535 shows an allometric relationship between the rat, dog and man. This would indicate that the transporter protein involved is conserved across these species and has similar affinity. However, marked reduction in clearance in the rabbit suggests the absence, or marked alteration, of the responsible protein in the hepatic sinusoidal membrane of this species. This finding may explain the common observation of reduced biliary excretion of acidic compounds in rabbits compared to other species [24, 25]. 

Telmisartan- As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Use telmisartan with caution in these patients. 

What makes prediction of drug elimination complex are the multiple possible pathways involved which explain why there is no simple in vitro clearance assay which predicts in vivo clearance. Because oxidative metabolism plays a major role in drug elimination, microsomal clearance assays are often used as a first line screen with the assumption that if clearance is high in this in vitro assay it is likely to be high in vivo. This assumption is often, but not always true because, for example, plasma protein binding can limit the rate of in vivo metabolism. However, compounds which have a low clearance in hepatic microsomes can be cleared in vivo via other mechanisms (phase II metabolism, plasmatic errzymes). Occasionally, elimination is limited by hepatic blood flow, and other processes like biliary excretion are then involved. The conclusion is that the value of in vitro assays needs to be established for each chemical series before it can be used for compound optimization. 

Nafcillin is primarily cleared by biliary excretion. Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion no dosage adjustment is required for these drugs in renal failure. Because clearance of penicillins is less efficient in the newborn, doses adjusted for weight alone result in higher systemic concentrations for longer periods than in the adult. 

Hypothyroidism developed within 2 weeks of rifampicin therapy in these patients and resolved when it was withdrawn. Rifampicin increases thyroxine clearance, possibly by enhancing hepatic thyroxine metabolism and the biliary excretion of iodothyronine conjugates. In healthy volunteers rifampicin reduces circulating thyroid hormone concentrations without affecting thyrotropin, suggesting that rifampicin directly reduces thyroid hormone concentrations. 

The longer biological half-life appears to be due to low-body clearance value (1.26 0.08 ml/kg/min). The cumulative urinary excretion of parbendazole for 5 days was found to be very low (0.475 0.144%). Fecal excretion of the drug was slightly higher (4.20 0.71% of the total administered dose) and may be suggestive of biliary excretion [43]. 

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. 

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