Metabolism hepatic first-pass

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

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). 

Data from a single study in dogs suggest that hepatic first-pass metabolism may limit systemic availability of the parent compound following oral exposure (Braeckman et al. 1983). Placental transfer of methyl parathion was demonstrated in pregnant rats 1-3 days before parturition. Thirty minutes after administration, both methyl parathion and methyl paraoxon were found in fetal brain, liver, and muscle methyl parathion, but not methyl paraoxon, was detected in placenta and maternal liver (Ackermann and Engst 1970). Methyl parathion binds reversibly to serum albumin, but is readily distributed to the tissues (Braeckman et al. 1980, 1983). 

Keywords Oral absorption Bioavailability Models of small intestine Intestinal permeability Intestinal perfusion techniques Intestinal versus hepatic first-pass metabolism... 

Sinko et al. [92] established an Intestinal and Vascular Access Port (IVAP) model where dogs were fitted with three intestinal catheters for site-specific administration to various section of the intestine (i.e. duodenum, ileum, and colon), one vascular catheter for access to the portal vein, and a peripheral vein (e.g. branchial) for IV access. The animals were allowed to recover for 2 weeks prior to initiation of studies. The extent of intestinal versus hepatic first-pass metabolism was determined by comparing blood levels following intra-duodenal (AUQ.d.) versus portal (AUVi.p.v.) versus intravenous (AUQ.V.) administration. The model also lends itself to a comparison of the impact of site-specific preferential absorption, and hence a determination of the optimal site for intestinal delivery. 

Ueda S, Yamaoka K and Nakagawa T (1999) Effect of Pentobarbital Anaesthesia on Intestinal Absorption and Hepatic First-Pass Metabolism of Oxacillin in Rats, Evaluated by Portal-Systemic Concentration Difference. J Pharm Pharmacol 51 pp 585-589. 

At present, despite the advantages offered by the buccal delivery route, such as the bypass of intestinal and hepatic first-pass metabolism for systemic delivery, very few pharmaceutical products employ this route of administration. The reasons that contribute to this situation include (1) high costs associated with development, (2) lack of standardized tests to identify drug candidates suitability for this route, (3) the limited understanding of the impact of metabolism and/or transporters found in the oral cavity mucosa on buccal delivery, and (4) the relatively small number of reports describing the usefulness and safety of excipients/permeation enhancers in humans [82, 83], Therefore, the... 

Different compartments pertaining to separate metabolic systems were assessed by selective injection as follows jugular vein to assess first-pass metabolism across lung, hepatic portal vein to assess hepatic first-pass metabolism, duodenum to assess intestinal mucosa metabolism, and carotid artery to assess immediate tissue distribution. 

Liver disease may decrease hepatic metabolism resulting in enhanced responses to parent chemicals however, for many compounds, metabolism is only slightly impaired in moderate to severe liver disease. Disease-induced alterations in clearance and volume of distribution often act in opposite directions with respect to their effect on half-life. Bioavailability may be markedly increased in liver disease with portal/systemic anastomosis (the connection of normally separate parts so they intercommunicate) so that orally administered chemicals bypass hepatic first-pass metabolism. Altered receptor sensitivity has been observed for some chemical substances in liver cirrhosis. When liver tissue repair is inhibited by chemical co-exposure, even an inconsequential level of liver injury may lead to fulminating liver failure from a nonlethal exposure of hepatotoxic-ants. (Several articles, as reviewed by Dybing and Spderlund 1999.)... 

Terazosin undergoes minimal hepatic first-pass metabolism nearly all of the circulating dose is in the form of parent drug. 

Valacyclovir is rapidly and completely converted to acyclovir by intestinal and hepatic first-pass metabolism. The bioavailabiUty of acyclovir following oral valacyclovir dosing is three to five times that resulting from oral acyclovir administration and is comparable to that of intravenous acyclovir. 

Answer Famciclovir is a prodrug that is rapidly converted to penciclovir, with a bioavaUabiUty of 77%. Maximal plasma concentrations of penciclovir are reached within 45 to 60 minutes of famciclovir administration. Mr. Smith developed an allergy to topical penciclovir when he was treated with this drug during college. This prior contact sensitization to penciclovir allowed him to develop an anaphylactoid reaction following the conversion of oral famciclovir to penciclovir by hepatic first-pass metabolism. 

It has variable absorption from GIT and has about 50% hepatic first pass metabolism. It is highly bound to plasma proteins. 

Propranolol is well absorbed after oral administration. Peak concentration occurs after 1-3 hrs after administration. Propranolol undergoes extensive hepatic first pass metabolism. The proportion of drug, reaching the systemic circulation increases as the dose is increased when the hepatic circulation may become saturated. It is rapidly distributed because it is lipid soluble. It can readily cross blood brain barrier (BBB). 

Losartan potassium is well tolerated. Bioavailability is 33% due to hepatic first pass metabolism. It is 98% plasma protein bound. It is activated in liver. Both parent compound and active compound are excreted in urine. 

They are administered through buccal, sublingual and parenteral routes. Skin ointments are also available. GTN is rapidly inactivated by hepatic first pass metabolism. So, oral tablets which are swallowed are ineffective. 

After oral administration hepatic first pass metabolism is less than isosorbide dinitrate, hence, systemic bioavailability is more. 

It is rapidly absorbed from intestine, undergoes high hepatic first pass metabolism. It readily crosses the blood brain barrier. 

The sublingual surface area is relatively small but has a rich blood supply. The major advantage of this route is avoidance of intestinal destruction and hepatic first pass metabolism. However, absorption can be highly variable critical factors are the residence time of the drug in the mouth and saliva flow. Premature swallowing or excessive saliva production preclude efficient absorption. Nitroglycerin, nifedipine, propranolol, and buprenorphine are all available as sublingual preparations. Rectal... 

In addition to increased overall bioavailability of lipophilic molecules, lymphatic transport of a drug provides further advantages, including avoidance of hepatic first pass metabolism, a potential to target specific disease states known to spread via the lymphatics, and improved plasma profile of the drug. 

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. 

FIGURE 1.6 In order to avoid extensive hepatic first-pass metabolism, nitroglycerin is given sublingually. GDN = 1,2- or 1.3-glyceryl dinitrate V.C. = vena cava. 

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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