First-pass metabolism and

Absorption of nadolol after po dosing is variable, averaging about 30%. The presence of food does not affect absorption. There is no hepatic first-pass metabolism and peak plasma concentrations are achieved in 3—4 h after po doses. About 30% of the plasma concentration is protein bound. The elimination half-hfe of nadolol is 20—24 h, allowing once a day dosing. The dmg is excreted unchanged by the kidneys and its excretion is delayed in patients having renal failure (98,99,108). 

Bioavailability is defined as the portion or fraction of a chemical that is available for biological action and is influenced by several factors including the molecular size and charge of a molecule, structural features of membranes, first pass metabolism, and therefore, bio availability can be influenced by the molecular structure of a chemical. This situation presents an opportunity for molecular designers to manipulate a chemical s structure to decrease bioavailability and consequently hazard. If the availability of a molecule can be decreased, the amount of chemical at the site of action is decreased which leads to decreased toxicity. 

Drug candidates that are intended for oral dosing need to have good ADME properties so that they can be dosed once or twice daily. The drug should be well absorbed, survive first pass metabolism, and have sufficiently low clearance. At the lead identification stage, the primary in vitro ADME assays employed are those that assess permeability and metabolic stability. There are a variety of assays available for both parameters, as described in the previous chapter. 

To reduce conjugative first-pass metabolism and increase the oral bioavailability of P-estradiol, estradiol-3-salicylate, and P-estradiol-3-anthranilate, ester prodrugs were synthesized and their oral bioavailabilities in dogs were evaluated... 

This type of information about a homologous series of drug candidates, when considered in light of the propensity of these compounds to undergo first-pass metabolism and/or liver clearance, allows pharmaceutical scientists to make more intelligent decisions about which compounds to move into animal studies. In addition, when an in vitro-in vivo correlation can be demonstrated for a series of compounds, the results of Caco-2 experiments can be used as a guide by medicinal chemists to make structural modifications to optimize oral bioavailability. 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

In summary, the scattered data available indicate that hemiester prodrugs generally undergo negligible hydrolysis at neutral pH in buffered solutions and in human plasma. In contrast, hydrolysis appears relatively fast in the presence of hepatic hydrolases. This would suggest limited first-pass metabolism and activation mediated mainly by liver hydrolases. 

The pharmacokinetics of ondansetron in man have been determined in healthy volunteers after single and repeat doses [84]. The clinical pharmacokinetics (Table 7.8) showed many similarities with the kinetics in animals, but also some important differences. Elimination is rapid, but less so than in animals. The volume of distribution is similar in animals and man. As in animals, the clearance of ondansetron in man is predominantly by metabolism. However, metabolic clearance in man is considerably lower than in animals, resulting in a lower first-pass metabolism and a significantly greater oral bioavailability of 60 %. Steady-state concentrations of ondansetron are consistent with the single-dose kinetics of the compound and show no evidence of significant accumulation. 

In opiate abuse, smack ( junk, jazz, stuff, China white mostly heroin) is self administered by injection ( mainUning ) so as to avoid first-pass metabolism and to achieve a faster rise in brain concentration. Evidently, psychic effects ( kick, buzz, rush ) are especially intense with this route of administration. The user may also resort to other more unusual routes opium can be smoked, and heroin can be taken as snuff (B). 

Metabolism - Ramelteon undergoes rapid, high first-pass metabolism, and exhibits linear pharmacokinetics. Several metabolites have been identified in human serum and urine. 

According to Gasteiger et al. [59], the correlation coefficient r between bioavailability and HIA is 0.498 for 161 compounds. This conclusion inspires us to propose the use of aqueous solubility, descriptors of HIA models, and some rule-based descriptors to predict first-pass metabolism, to model bioavailability. Another research direction for the prediction of oral bioavailability is to develop separate prediction models for different components involved in oral bioavailability, including passive transcellular transport, paracellular transport, carrier-mediated transport, and first-pass metabolism, and then integrate them together. At present, the development of an integrated model is really difficult or even impossible because the predictions for some mechanisms involved in oral bioavailability are really unreliable. 

The concomitant intake of grapefruit juice increases the concentration of many drugs (e.g., testosterone, sildenafil) in humans. Such actions appear to be mediated mainly by the suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine. The resultant diminished first-pass metabolism and increased bioavailability can lead to increased drug levels in the blood. Because sildenafil is metabolized by CYP3A and to a... 

It is rapidly absorbed and undergoes extensive first pass metabolism and excreted through kidney and faeces. 

It is a cromolyn analogue. It is an antihistaminic (H antagonist) and probably inhibits airway inflammation induced by platelet activating factor (PAF) in primate. It is not a bronchodilator. It is used in asthma and symptomatic relief in atopic dermatitis, rhinitis, conjunctivitis and urticaria. It is absorbed orally and well tolerated. Bioavailability is 50% due to first pass metabolism and is primarily metabolized. The common side effects include dry mouth, sedation, dizziness and nausea. 

While uncontrolled topical delivery of proteins and peptides for local application such as open wound healing is easily achieved, it is much more challenging to use transdermal delivery systems to deliver protein across intact skin. In theory, transdermal delivery could provide constant drug release for days, avoids first-pass metabolism, and could allow drug effects to be rapidly terminated by simply removing... 

Chronic alcohol ingestion can cause cirrhosis, reducing hepatic CYP enzyme concentration and liver mass, and causing portacaval shunting. These effects will result in increased plasma drug levels due to both greater bioavailability (due to reduced first pass metabolism) and due to decreased clearance. Thus, dose adjustment is necessary and should be guided by TDM when possible. 

Beta-adrenoceptor antagonists, particularly propranolol, have been shown to be effective for anxiety symptoms particularly in situational anxiety and GAD. Buspirone, an azaspirodecanedione, is an agonist at 5-HTlA receptors and seems to have anxiolytic effects, though it is less potent than the BDZs and the effects take up to three weeks to become evident. There is high first pass metabolism and a considerable proportion of the effect is due to a metabolite (1-PP). The principal adverse effects of buspirone are nausea, gastrointestinal upset and headache. Antidepressant drugs, both the older tricyclic antidepressants and the newer drugs, have been demonstrated to have anxiolytic effects in mixed anxiety-depressive patients, GAD and panic disorder. 

Pharmacokinetic characteristics of prazosin are listed in Table 11-2. Terazosin is also extensively metabolized but undergoes very little first-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours. 

Effective oral dosages are higher than intravenous dosage because of first-pass metabolism and range from 120 mg to 640 mg daily, divided into three or four doses. 

In order to overcome these issues, various noninvasive routes are tested for the delivery of peptides. The oral mucosa due to its high vascularity, avoidance of hepatic first-pass metabolism, and the absence of degradative enzymes normally present in the GI tract has been explored as a suitable route for peptide delivery. Several studies of peptide absorption through the oral mucosa have been conducted, and the results have been impressive in some cases, and not in the others. The development of mucoadhesive systems for buccal and sublingual delivery has increased the absorption and bioavailability of peptides, and various formulations have been developed using these systems. 

Pharmacokinetic data is used to differentiate between active substances with good and poor pharmacokinetic characteristics. For example, substances with poor absorption, high first pass metabolism and an unsuitable half-life (too long or too short) will normally be discarded in favour of substances with more appropriate pharmacokinetic properties. 

One final consideration of drug interactions involving intestinal CYP3A is the fact that differential modulation of intestinal and hepatic CYP3A is possible. Simultaneous inhibition of intestinal first-pass metabolism and stimulation or induction of hepatic first-pass metabolism has been reported for the interaction between the herbal supplement echinacea (Echinacea purpurea root) and... 

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