Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. Cycling is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile. Factors affecting biliary excretion include drug characteristics (chemical structure, polarity and molecular size), transport across sinusoidal plasma membrane and canniculae membranes, biotransformation and possible reabsorption from intrahepatic bile ductules. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Bioavailability is also affected by the extent of intestinal absorption, gut-wall P-glycoprotein efflux and gut-wall metabolism. Recently, there has been a considerable increase in our understanding of the role of transporters, of gene expression of intestinal and hepatic enzymes, and of hepatic zonation. Drugs, disease and genetics may result in induced or inhibited activity of transporters and metabolising enzymes. Reduced expression of one transporter, for example hepatic canalicular multidrug resistance-associated protein (MRP) 2, is often associated with enhanced expression of others, for example the usually quiescent basolateral efflux MRP3, to limit hepatic toxicity. In addition, physiologically relevant pharmacokinetic models, which describe enterohepatic recirculation in terms of its determinants (such as sporadic gall bladder emptying), have been developed. In general, enterohepatic recirculation may prolong the pharmacological effect of certain drugs and drug metabolites. Of particular importance is the potential amplifying effect of enterohepatic variability in defining differences in the bioavailability, apparent volume of distribution and clearance of a given compound. Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling.

Enterohepatic circulation: physiological, pharmacokinetic and clinical implications.

Determining the biliary clearance of drugs in humans is very challenging because bile is not readily accessible due to the anatomy of the hepatobiliary tract. The collection of bile usually is limited to postsurgical patients with underlying hepatobiliary disease. In healthy subjects, feces typically are used as a surrogate to quantify the amount of drug excreted via nonurinary pathways. Nevertheless, it is very important to characterize hepatobiliary elimination because this is a potential site of drug interactions that might result in significant alterations in systemic or hepatic exposure. In addition to the determination of in vivo biliary clearance values of drugs, the availability of in vitro models that can predict the extent of biliary excretion of drugs in humans may be a powerful tool in the preclinical stages of drug development. In this review, recent advances in the most commonly used in vivo methods to estimate biliary excretion of drugs in humans are outlined. Additionally, in vitro models that can be employed to investigate the molecular processes involved in biliary excretion are discussed to present an updated picture of the new tools and techniques that are available to study the complex processes involved in hepatic drug transport.

/pdf/methods-to-evaluate-biliary-excretion-of-drugs-in-humans-an-3fg6cy8ns6.pdf

Methods to evaluate biliary excretion of drugs in humans: an updated review.

The effects of Chuanxiong on the pharmacokinetics of warfarin in rats after biliary drainage.

Plasma levels and urinary excretion of lormetazepam (Noctamid ®-ampoules; 2 mg/10 ml) were studied after i.v. (0.015 mg/kg b.w.) and after p.o (0.03 mg/kg b.w.) administration of the drug to five patients with cirrhosis of the liver (C) and to five young male volunteers (N).

Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers.

In the present study, we investigated the relationships between several
 molecular properties and bioavailability data for seven of the most commonly
 prescribed angiotensin II receptor antagonists (also known as angiotensin II
 receptor blockers (ARBs) or sartans), candesartan, eprosartan, irbesartan,
 losartan, olmesartan, telmisartan and valsartan. The molecular descriptors of
 ARBs are:, aqueous solubility (logS values), polar surface area (PSA),
 molecular weight (Mw), volume value (Vol), lipophilicity (logP values) and
 the acidity descriptor (pKa1). The respective descriptors were calculated
 using four different software packages. The relevant bioavailability data
 were obtained from literature. Among calculated molecular descriptors, simple
 linear regression analysis showed the best correlation between
 bioavailability data and the lipophilicity descriptor, logP (R2 = 0.568).
 Multiple linear regression established good correlations between
 bioavailability and the lipophilicity descriptor, logP, using the molecular
 weight, Mw, or the acidity descriptor, pKa1, as an additional, independent
 variable (with R2 0.661 and 0.682, respectively). Finally, excluding
 candesartan from the calculations resulted in a very good correlation (R2 =
 0.852) between the remaining ARB bioavailability and molecular descriptors
 MlogP and Mw as independent variables, determined by multiple linear
 regression. [Projekat Ministarstva nauke Republike Srbije, br. TR34031]

/pdf/relationship-between-the-bioavailability-and-molecular-3t9jk8z6nu.pdf

Relationship between the bioavailability and molecular properties of angiotensin II receptor antagonists

The pharmacokinetics of lormetazepam (LMA) was studied in five patients with intact and interrupted enterohepatic recirculation (EHR) after an oral dose of 0.03 mg/kg given as solution. The disposition of lormetazepam in plasma was characterized by peak plasma levels of 14-60 ng/ml after 20-40 min. Peak plasma levels of the unchanged drug were higher (p less than 0.05) in case of interrupted EHR as compared to intact EHR. The areas and the plasma levels vs time curves of lormetazepam and its glucuronide were not statistically different and the oral clearance of lormetazepam was similar in both parts of the study (median 3.1 and 3.6 ml/min/kg). In case of interrupted EHR, 23-58% of dose was excreted as lormetazepam and its glucuronide with the urine during 24 h, in case of intact EHR, the urinary dose fraction was 9-35% (p less than 0.05). The 24 h postdose-bile fraction contained only 0.3-2.8% of the oral lormetazepam dose in form of the drug and its glucuronide. In conclusion, only negligible amounts of lormetazepam are excreted in bile. The demethylated metabolite lorazepam was not detectable in the biological samples investigated.

Minimal biliary excretion and enterohepatic recirculation of lormetazepam in man as investigated by a new nasobiliary drainage technique.

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Minimal biliary excretion and enterohepatic recirculation of lormetazepam in man as investigated by a new nasobiliary drainage technique.