First-pass clearance

Clearance is a critical parameter because of its role in determining a drug s dose size and frequency. First-pass clearance in combination with absorption determines a compound s bioavailability. Clearance and absorption in combination with potency determine dose size. Clearance and volume of distribution determine half-life, and thus dosing frequency. 

Prediction of bioavailability from molecular structure is quite difficult, since bioavailability depends on absorption and first-pass clearance [141]. By applying fuzzy adaptive least squares , Yoshida and Topliss generated a QSAR model using logD at pH 7.4 and 6.5 as input for physicochemical properties and the presence/absence of certain functional groups as structural input. They achieved a classification of drugs into one of four bioavailability categories with an overall accuracy of 60% [142]. 

First-pass clearance can be tracked to gut-stability or metabolism by phase I and then either direct clearance or clearance of the metabolite by phase It enzymes or biliary, renal or plasma clearance. Metabolite stability by phase I enzymes include inhibition, induction, regiospecificity, lability or affinity toward several cytochrome... 

The oral absorption of tipranavir is limited, and the bioavailability is increased with a high-fat meal. Its binding to plasma proteins is more than 99.9% where it binds to both ai -glycoprotein and albumin. Tipranavir is metabolized by cytochrome P-450 isoenzyme CYP3A4. Ritonavir decreases its first-pass clearance, and most of the drug is excreted in feces. In combination with other antiretroviral agents, tipranavir coadministered with ritonavir is indicated for HIV infection in patients who have received prior HIV treatment or have highly resistant HIV strains. 

Fluvoxamine increases the systemic availability of oral melatonin, probably by reducing its first-pass clearance (34). In a crossover study in seven healthy subjects, serum melatonin concentrations were increased by fluvoxamine but not citalopram (35). In another study fluoxetine, paroxetine, citalopram, imipramine, and desipramine did not affect the biotransformation of melatonin at therapeutic concentrations in vitro (36). 

The pharmacokinetic profiles of these agents suggested that esomeprazole had inhibited P glycoprotein, reducing the normal first-pass clearance of atorvastatin (32). 

Birkett, D. J. (1991). Bioavailability and first pass clearance. Australian Prescriber, 14, 14-16. 

STATINS PROTON PUMP INHIBITORS Possible T efficacy and adverse effects of atorvastatin Inhibition of P-gp, reducing first-pass clearance Monitor closely... 

Although labetalol is completely absorbed from the gut, there is extensive first-pass clearance bioavailability may be increased by food intake. The rate of hepatic metabolism of labetalol is sensitive to changes in hepatic blood flow. The various isomers have dijferent elimination kinetics. 

Bioavailability is a measure of the extent of a drug reaching the systemic circulation from its point of administration. From an oral dose therefore, it depends both on the degree of absorption and first pass clearance experienced by the dose. Assuming good estimates of absorption and predicted clearance are available, the bioavailability (F) can be predicted using eqn (13.11). 

A study in 20 patients undergoing spinal anaesthesia with tetracaine found that propofol sedation (as measured by bispectral index monitoring (BIS)) was enhanced when adrenaline was added to the intrathecal tetracaine." A study in sheep found that adrenaline, noradrenaline and dopamine decreased propofol concentrations during a continuous propofol infusion, with the result that propofol anaesthesia was reversed. This was thought to be due to increased first pass clearance of propofol secondary to increased cardiac output. It was concluded that this could be of clinical importance if propofol is used in hyperdynamic circulatory conditions induced by either catecholamine infusions or disease states such as sepsis. ... 

A study in healthy subjects found that the bioavailability of oral lidocaine was markedly lower in smokers (mean AUCs of 15.2 and 47.9 micrograms/mL per minute in 4 smokers and 5 non-smokers respectively), but when the lidocaine was given intravenously only moderate differences were seen. The reason for the differences is probably due to liver enzyme induction caused by components of tobacco smoke. With oral lidocaine this could result in increased first-pass hepatic clearance. In the case of intravenous lidocaine, first-pass clearance is bypassed, and the enzyme induction was opposed by a smoking-related decrease in hepatic flow. In practical terms this interaction is unlikely to be of much importance since lidocaine is not usually given orally. 

It is clear from the transplant literature that graft survival requires portal blood flow and the hepatotrophic effect of hepatectomy is well established(33). To take full advantage of circulating hepatotropic factors, we created portocaval shunts (PCS) in the recipient rats to eliminate first pass clearance of these factors by the native liver. We therefore repeated the studies with prevascularized polymeric foams, but additionally created a PCS in one group of animals, a 70% hepatectomy in another group of animals, and both a PCS and hepatectomy in yet another group studied. 

Zhang Q-Y, Fang C, Dunbar D, Zhang J, Kaminsky LS, Ding X. An intestinal epithelium-specific cytochrome P450 reductase-knockout mouse model Direct evidence for a role of intestinal cytochromes P450 in first-pass clearance of oral nifedipine. Drug Metab Dispos 2009 37 651-657. 

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