Humans renal clearance

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. 

As described above, it will be normal to assume that the dose interval is 24 hours, i.e., once-a-day dosing. Absorption can be estimated with good confidence from absorption in the rat (see Section 6.1). Clearance is the sum of the predicted hepatic, renal, biliary and extrahepatic clearance. Hepatic clearance can be derived from in vitro studies with the appropriate human system, using either microsomes or hepatocytes. We prefer to use an approach based on that described by Houston and Carlile [83], Renal clearance can be predicted allometrically (see section 6.8.1). The other two potential methods of clearance are difficult to predict. To minimize the risks, animal studies can be used to select compounds that show little or no potential for clearance by these routes. As volume can be predicted from that measured in the dog, after correction for human and dog plasma protein binding (see Section 6.2), it is possible to make predictions for all of the important parameters necessary. 

Benowitz N, Lessov-Schlaggar C, Swan G (2008b) Genetic Influences in the Variation in Renal Clearance of Nicotine and Cotinine. Clin Pharmacol Ther 84(2) 243-247 Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S (1997) Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282(1) 7-13... 

Hepatic metabolism and excretion in the bile play major roles in the elimination of both vinblastine and vincristine in humans (52) small amounts of vincristine and vinblastine, of the order of 10% of the administered dose, are excreted unchanged in urine. Renal clearance of vinblastine has been reported to be less than 10% of total serum clearance 53). Vinblastine has been reported to inhibit a polymorphic cytochrome P-450 system in human hepatic microsomes, but the concentrations required were much higher than those observed in clinical settings (54). 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Excretion - Excretion of caspofungin and its metabolites in humans was 35% in feces and 41% in urine. A small amount of caspofungin is excreted unchanged in urine (approximately 1.4% of dose). Renal clearance of parent drug is low (approximately 0.15 mL/min), and total clearance of caspofungin is 12 mL/min. 

A full characterization of the metabolic pathways of CPT-11 in human cancer patients has not been undertaken. The incomplete recovery of the irinotecan dose based on urine and bile determinations of irinotecan, SN-38, and SN-38 glucuronide suggests the presence of additional unidentified metabolites. Recently, a major metabolite, 7-ethyl-10-[4-A-(5-aminopenatoic acid)-l-piperidino]carbonyloxycamptothecin, has been identified in dogs and humans, suggesting the presence of an additional metabolic pathway (18). Renal clearance has not been reported to be a major route of elimination for these compounds in humans. 

PAM is eliminated rapidly by man and animals. In humans, biologic half-life is about 1-2 h.l This short half-life is due in part to metabolism, but more to the fact that renal clearance approaches 700 ml/min, - i.e., almost that of j>-aminohippuric acid (PAH). Investigators have therefore suggested that 2-PAM might be secreted into the urine. 4,50,100,108... 

Disposition In healthy subjects, renal clearance of eptihbatide accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptihbatide, deamidated eptihbatide, and other, more polar metabohtes. No major metabohtes have been detected in human plasma. 

Disposition FSH metabolism following administration of Gonal-F has not been studied in humans. FSH renal clearance was 0.07 liter/h after intravenous administration representing approximately 1/8 of total clearance. 

Digoxin is not extensively metabolized in humans almost two thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance and the half-life is 36-40 hours in patients with normal renal function. Equations and nomograms are available for adjusting digoxin dosage in patients with renal impairment. 

Renal clearance accounts for 61% of the total body clearance of ciprofloxacin in humans (350). Coadministration of probenecid reduces the total body and renal clearance to 59% and 36% of the control value, respectively, but has no effect on the nonrenal clearance (336). The transporters involved in the renal elimination of ciprofloxacin remains unknown. 

Renal clearance of ciprofloxacin averages 300 179 mL/min in adults with normal renal function, and the drug is 16-43% bound to serum protein in vitro. It crosses the placenta and is distributed into the amniotic fluid in humans. The usual human dosage has not revealed evidence of harm to the fetus. 

Our findings in this study are in harmony with the concept that L-cystathionine is an intermediate in the formation of cystine from methionine in man. Direct evidence for the existence of cystathionine in man was provided by the demonstration by Tallan, Moore, and Stein (13) of the occurrence of L-cystathionine in extracts of human brain. Moreover, cases of human cystathioninuria have been reported by Harris, Penrose, and Thomas (9) and by Frimpter, Haymovitz, and Horwith (8). The latter authors have also stated that an increased renal clearance of cystathionine is not observed in cystinuria. It is of considerable interest, however, that the mixed disulfide of L-cysteine and L-homo-... 

DNA sequence The nucleotide sequence data are available from the EMBL, GenBank, and DDBJ Nucleotide Sequence Databases under accession number X52255 Half-life About 20 min (experimentally determined for human cystatin C in rat plasma. The similarity in distribution volume and renal clearance between human cystatin C and acknowledged markers of human glomerular filtration, i.e., iohexol and 51 Cr-EDTA, suggests that the substances are eliminated at the same rate in humans with a half-life of approximately 2 h in individuals with normal renal function)... 

In more concrete termS/ if m = 0.7 for the renal clearance of a particular drug/ the clearance per unit body weight in a 20-gram mouse would expected to be 1(70/000)7 (20)]° = 12 times that in 70-kg human. If the volume of distribution is similar on a liter per kilogram basis between the two species (such as body water) and the drug is cleared only by the kidney/ theii/ as a rough approximation/ the elimination half-life would be 12 times longer in the human. ThuS/ 1 hour in a mouse would be pharmacokinetically equivalent to 12 hours in a human. 

What is the underlying cause for these interspecies differences For equal doses, differences in plasma AUC values simply indicate differences in total body clearance. Renal and metabolic elimination processes are the major contributors to total body clearance. When allometric scaling is used as described in Chapter 30, renal clearance tends to exhibit only small differences across species, whereas there are many examples of interspecies differences in metabolism. Further, across many drug categories, metabolism is quantitatively more important than is renal elimination. Therefore, more emphasis on inter species differences in drug metabolism could improve Phase I studies. The next two sections provide specific examples of the impact of monitoring metabolism during early human studies. 

A limited amount of work has been published on this topic. For cromakalim (1), a h.p.l.c. method has been developed [97] to detect unlabelled (1) and its major metabolites in human urine, as renal clearance is the principal excretory route. The metabolic fate of levcromakalim (2) has been determined [98], and the resulting metabolites have been identified in human urine using C-levcromakalim (see Figure 9.2). The compound was extensively absorbed, and in human plasma levcromakalim (2) accounted for the majority of drug-related material, while no evidence was found for any in vivo interconversion of levcromakalim (2) to the 3R,45-enantiomer [98]. 

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