Presystemic clearance

Oda, Y., Kharasch, E. D., Metabolism of methadone and levo-a-acetyl-methadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4) potential contribution of intestinal metabolism to presystemic clearance and bioactivation, J. Pharmacol. Exp. Ther. 2001, 298, 1021-1032. 

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. 

C., Warzok, R., Engel, G. Weitschies, W., Cascorbi, I., Kroemer, H.K. and Siegmund, W. (2004) CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clinical Pharmacology and Therapeutics, 75, 213-222. 

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. 

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... 

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). 

The intrinsic kinetic properties of the victim drug also influence the potential clinical consequences of an interaction. For orally administered medications that undergo significant presystemic extraction, impairment of clearance by a CYP inhibitor may produce increases in bioavailability (reduced presystemic extraction) as a consequence of reduced clearance. The effects may be particularly dramatic for CYP3A substrates (such as triazolam, midazolam, or buspirone) that undergo both hepatic and enteric presystemic extraction. As an example, coadministration of the CYP3A inhibitor ketoconazole with triazolam produced very large increases in area under the plasma concentration-time curve... 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

Since the introduction of transdermal scopolamine,f" many transdermal delivery systems have been developed for systemic activity. Major advantages claimed for this drug delivery route include continuous release of drug over a specified period, low presystemic clearance, facile drug withdrawal by simply removing the device, and good patient convenience and compliance. 

Kemp DC, Fan PW, Stevens JC. Characterization of raloxifene glucuronidation in vitro Contribution of intestinal metabolism to presystemic clearance. Drug Metab Dispos. 2002 30(6) 694-700. 

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... 

The two main sources of stereoselectivity in drug disposition are the circulatory proteins and enzymes in both the gastrointestinal tract and the liver. Both binding of drugs to proteins and metabolism by various isozymes are, therefore, often stereoselective. Many examples of stereoselective systemic clearance and presystemic metabolism exist (see Chapters 6 and 7). For a few classes of drugs, metabolism may include chiral inversion (see Chapter 8). This, if unidirectional, adds to the overall stereoselectivity in disposition of drugs. Bidirectional bioinversion (see Chapter 8), on the other hand, similar to chemical racemization (thalidomide, see Chapter 5), may diminish stereoselectivity. 

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