Metabolism, hepatic Presystemic

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. 

Hydralazine undergoes hepatic (presystemic) metabolism in most species and so its bioavailability is poor following oral administration despite being well absorbed. It should be administered by i.v. injection, where clinical effects lasting 4h can be seen (Bertone 1988). 

It is apparent, therefore, that the presystemic metabolism of Hf is reduced in both the fed state and after co-administration with KC. The effects of KC co-administration on hepatic elimination were not studied in the investigation described here, precluding quantification of the relative roles of prehepatic and hepatic presystemic metabolism to the altered metabolic profile seen after KC co-administration. In contrast, recent examination of Hf pharmacokinetics after fed and fasted intravenous administration revealed a decrease in Hf systemic CL of only approximately 15% after fed administration, suggesting that the almost complete inhibition of Hf metabolism in the fed state must be a result of extra... 

Hepatic presystemic metabolism is most easily understood when liver is the sole organ of drug elimination. Under these conditions, the clearance of the drug, as determined following intravenous administration of the drug, is equal to... 

If the fraction of the oral dose is absorbed and then subjected to hepatic presystemic metabolism, the... 

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. 

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. 

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... 

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],... 

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). 

Equation 9.95 shows that the systemic availability of the drug depends on the hepatic extraction ratio of the drug, and those drugs with low hepatic extraction ratios, such as antipyrine, tolbutamide, and warfarin, undergo little presystemic metabolism. 

Presystemic metabolism (Gl/hepatic first-pass effects)... 

Atorvastatin is readily absorbed after the oral administration. Multiple daily dosages in the form of 2.5-80 mg capsules produce a maximum steady state concentration (Cmax) of 1.95-252 /ig/ml within 1-2 h. The AUC increases in proportion to the dose of atorvastatin, but the increase in Cmax is greater than for the proportional dose. The low systemic availability is attributed to the presystemic clearance in gastrointestinal mucosa and/or hepatic first pass metabolism. Food significantly... 

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