Metabolism presystemic

Pharmacokinetic Definition of Intestinal Absorption (fa), Presystemic Metabolism (Ec and Eh) and Absolute Bioavailability (F) of Drugs Administered Orally to Humans... 

Interestingly, slices of human small intestine also metabolized tegaserod to the N-glucuronides, suggesting a contribution of the small intestine to the presystemic metabolism of the drug. 

If the apparent plasma clearance (dose/area under the plasma concentration-time curve, equivalent to true clearance/fraction of dose absorbed) gives an implausibly high value of clearance (e.g., greater than hepatic and renal plasma flow), it is likely the bioavailability is low. However, this could be due to presystemic metabolism in addition to low absorption. 

Pharmacokinetic Poor oral absorption Marked presystemic metabolism Short duration of action Unfavorable distribution in the body... 

Metabolism - No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or presystemic metabolism. 

Hepatic function impairment Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon was reduced by 70% and 87% in compensated and decompensated cirrhotic patients, respectively. 

It is rapidly and almost completely absorbed following oral administration. It undergoes significant presystemic metabolism, all the metabolites are pharmacologically inactive. 

It is readily and completely absorbed from the GIT following oral administration with no presystemic metabolism. 

Drug Presystemic metabolism Active metabolites Protein binding Dose (mg) Half-life (h) ... 

Efflux systems and presystemic metabolism are, beside other reasons, responsible for low bioavailability of orally administered drugs. Presystemic metabolism itself can be divided into three subtypes luminal metabolism, first-pass intestinal metabolism, and first-pass hepatic... 

An increasing body of evidence has shown that certain lipids and excipients found in many lipid-based formulations are capable of inhibiting both P-gp mediated drug efflux and presystemic metabolism in the enterocyte. This inhibition may increase the bioavailability of a drug coadministered with such lipid-based vehicle. 

As reviewed in this chapter, certain means can be utilized to improve the bioavailability of lipophilic drugs, whether by formulative approach or molecular changes strategies. These means present a number of attractive propositions to the scientist, ranging from an enhancement of drug dissolution and solubilization by lipid-based formulation, increased solubility via the synthesis of a prodrug, specific delivery to the intestinal lymphatics, and reduction in enterocyte-hepatic presystemic metabolism and efflux systems. 

Aungst, B.J. 1993. Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism. J Pharm Sci 82 979. 

Oxybutynin has a relatively low oral bioavailability (6%) due to an extensive first-past presystemic metabolism after administration [194], Indeed, the absence of intact oxybutynin in urine suggests that the major elimination pathway of this drug is hepatic metabolism [195]. The compound is readily converted to its stable toxic metabolite, iV-desethyloxybutynin by cytochrome P450-mediated oxidation [196], Following oral administration of oxybutynin, peak plasma concentrations are reached within 1 h. The short half-life of this drug (less than 2 h), when administered as a conventional oral formulation, necessitates multiple 5 mg daily dosing [197],... 

Transdermal delivery is a noninvasive intravenous infusion of drug to maintain efficacious drug levels in the body for predictable and extended duration of activity. Diffusion-controlled transdermal systems are designed to deliver the therapeutic agent at a controlled rate from the device to and through the skin into the systemic circulation. This route of administration avoids unwanted presystemic metabolism (first-pass effect) in the GI tract and the liver. Patient satisfaction has been realized through decreased... 

Zaleplon is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations are attained within approximately 1 h after oral administration. Although zaleplon is well absorbed, its absolute bioavailability is approximately 30% because it undergoes significant presystemic metabolism [24],... 

The pharmacokinetics of zaleplon in elderly subjects is not significantly different from that in young healthy subjects [38]. Nevertheless, Drover [39] contends that this conclusion may indicate a lack of adequate studies in this area. As described earlier, zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon is reduced, and the drug effect is prolonged in patients with hepatic impairment [40]. The clearance of zaleplon is not altered in patients with mild to moderate renal insufficiency [40] (Tab. 3). 

For orally administered peptides and proteins, the gastrointestinal tract is the major site of metabolism. Presystemic metabolism is the primary reason for their lack of oral bioavailability. Parenterally administered peptides and proteins, however, may also be metabolized in the intestinal mucosa following intestinal secretion. At least 20% of the degradation of endogenous albumin takes place in the gastrointestinal tract [13]. 

A metabolite may be formed as a result of gut wall or other presystemic metabolism. If the metabolite contributes meaningfully to safety and/or efficacy, the metabolite and the parent drug should be measured. When the relative activity of the metabolite is low and does not contribute meaningfully to safety and/or efficacy, it does not need to be measured. The parent drug measured in these BE studies should be analyzed using a Cl approach. The metabolite data can be used to provide supportive evidence of comparable therapeutic outcome. 

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