Clearance extraction

Figure 5 Schematic of the extraction of a drug by an eliminating organ at steady state, illustrating the interrelationships between blood clearance, extraction ratio, and organ blood flow. See the text for appropriate equations. Source From Ref. 1.

It is truly possible to imagine the characteristics of an ideal radiopharmaceutical only in the context of a specific disease and organ system to which it might be appHed. Apart from the physical factors related to the radioisotope used, the only general characteristic that is important in defining the efficacy of these materials is the macroscopic distribution in the body, or biodistribution. This time-dependent distribution at the organ level is a function of many parameters which may be divided into four categories factors related to deUvery of the radiopharmaceutical to a particular tissue factors related to the extraction of the compound from circulation factors related to retention of the compound by that tissue and factors deterrnined by clearance. The factors in the last set are rarely independent of the others. 

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

To further investigate the role of the liver in brevetoxin metabolism, PbTx-3 was studied in the isolated perfused rat liver model (27, 28). Radiolabeled PbTx-3 was added to the reservoir of a recirculating system and allowed to mix thoroughly with the perfusate. Steady-state conditions were reached within 20 min. At steady-state, 55-65% of the delivered PbTx-3 was metabolized and/or extracted by the liver 26% remained in the effluent perfusate. Under a constant liver perfusion rate of 4 ml/min, the measured clearance rate was 0.11 ml/min/g liver. The calculated extraction ratio of 0.55 was in excellent agreement with the in vivo data. Radioactivity in the bile accounted for 7% of the total radiolabel perfused through the liver. PbTx-3 was metabolized and eliminated into bile as parent toxin plus four more-polar metabolites (Figure 3). Preliminary results of samples stained with 4-(p-nitrobenzyl)-pyridine (29) indicated the most polar metabolite was an epoxide. 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

Despite their potential health-promoting effects as dietary antioxidants, the fate of betalains in humans has been poorly studied. Betalain bioavailability was first demonstrated in humans by the appearance of betacyanins in urines after ingestion of beetroot extract" and red beet juice," indicating that these compounds are indeed absorbed. Although intact betacyanins (betanin and isobetaiun) appeared rapidly in human urine with a maximum excretion rate observed within 2.5 to 8 hr," betacy-anin recoveries in human urine were usually low (< 1% of the dose) over 24 hr postdose, suggesting that either the bioavailabifity of betacyaiuns from red beetroot is low or that renal clearance is a minor excretion route for these compounds. 

This indicates that the first-pass availability is a function of organ flow, protein binding, and intrinisic clearance of the organ. When fu CLint Q (i.e., when we have relatively large extraction ratios), the first-pass bioavailability is equal to... 

Under this circumstance, the first-pass bioavailability is inversely proportional to the unbound fraction, and changes in the binding are expected to have a significant effect. It is also clear that changes in both the blood flow and the intrinsic clearance of the first-pass organ may have a significant effect when the extraction ratio is high (fu CL n Q). On the other hand, if... 

Another refinement, that avoids the necessity of developing suitable fecal extraction and chromatographic methods, is to dose the radiolabeled compound by both the i.v. and p.o. routes in two separate studies. Knowing that, by definition, the whole of the i.v. dose must have been bioavailable, a comparison of the proportion of the dose in the urine after the two different routes allows estimation of the percent absorbed. An analogous approach can be used without the use of a radiolabel, when the urine from the two studies is analyzed either for the parent compound or, more usually, for a major common metabolite. Assuming quantitatively identical clearance after both the i.v. and p.o. doses, the ratio of the amounts of analyte in the two experiments gives the absorption. 

The drawback of this approach is that it is essentially empirical, and does not allow for differences in metabolic clearance between the species, i.e., it assumes that clearance is proportional to blood flow. This works well for compounds that are highly extracted in the liver, and/or where passive renal clearance is the major pathway [5, 68]. An approach for compounds that are actively secreted into the urine has also been proposed [69], although the precise values of some of the physiological scaling factors have been questioned [70]. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

T or si Free fraction of highly plasma protein-bound drugs si Clearance and T t1/2 for some oxidatively metabolized drugs si Clearance and T t1/2 for drugs with high hepatic extraction ratios si Clearance and T t 2 for renally eliminated drugs and active metabolites... 

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. 

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