Metabohsm hepatic

The principal route of macroHde excretion is by way of the Hver. Effects of macrohdes on hepatic metaboHc enzymes, particularly cytochrome P-450, have been studied in order to identify and reduce potential interference with metaboHsm of other dmgs (21—23,444—447). Several macrohdes are initially... 

About 97% of po dose is absorbed from the GI tract. The dmg undergoes extensive first-pass hepatic metaboHsm and only 12% of the po dose is bioavailable. More than 95% is protein bound and peak plasma concentrations are achieved in 2—3 h. Therapeutic plasma concentrations are 0.064—1.044 lg/mL. The dmg is metabolized in the Hver to 5-hyroxypropafenone, which has some antiarrhythmic activity, and to inactive hydroxymethoxy propafenone, glucuronides, and sulfate conjugates. Less than 1% of the po dose is excreted by the kidney unchanged. The elimination half-life is 2—12 h (32). 

Absorption is complete and bioavailabihty is about 100% at steady state during continuous po dosing. There is extensive hepatic first-pass metabohsm to norlorcainide and hydroxylated metaboUtes. Nodorcainide is equipotent and equieffective to lorcainide in antiarrhythmic activity. 

Acebutolol is well absorbed from the GI tract. It undergoes extensive hepatic first-pass metabohsm. BioavailabiUty of the parent compound is about 40%. The principal metaboflte, A/-acetylacebutolol, has antiarrhythmic activity and appears to be more cardioselective. Binding to plasma proteins is only 26%. Peak plasma concentrations of acebutolol are achieved in 2.5 h, 3.5 h for A/-acetylacebutolol. The elimination half-Hves of acebutolol and its metabohte are 3—4 and 8—13 h, respectively. The compounds are excreted by the kidneys (30—40%) and by the Hver into the bile (50—60%). About 40% of the amount excreted in the urine is unchanged acebutolol, the rest as metabofltes (32). 

Po adrninistered nifedipine is almost completely absorbed. The onset of action is 20 min and peak effects occur at 1—2 h. The principal route of elimination is through hepatic metaboHsm by oxidation to hydroxycarboxyHc acid and the corresponding lactone. These metaboHtes are pharmacologically inactive. Almost 70—80% of dmg is eliminated in the urine during the first 24 h. About 15% is excreted in the feces. The elimination half-life of nifedipine is about 1—2.5 h (1,98,99). Frequency of occurrence of side effects in patients is about 17% with about 5% requiring discontinuation of therapy (1,98,99). 

Nicardipine is almost completely absorbed after po adrninistration. Administration of food decreases absorption. It undergoes extensive first-pass metaboHsm in the Hver. Systemic availabiHty is dose-dependent because of saturation of hepatic metaboHc pathways. A 30 mg dose is - 35% bioavailable. Nicardipine is highly protein bound (>95%). Peak plasma concentrations are achieved in 0.5—2.0 h. The principal path of elimination is by hepatic metaboHsm by hydrolysis and oxidation. The metaboHtes are relatively inactive and exert no pharmacological activity. The elimination half-life is 8.6 h. About 60% of the dose is excreted in the urine as metaboHtes (<1% as intact dmg) and 35% as metaboHtes in the feces (1,2,98,99). 

Electrotransport technology offers a number of benefits for therapeutic appHcations, including systemic or local adininistration of a wide variety of therapeutic agents with the potential adininistration of peptides and proteins long-term noninvasive administration, improving convenience and compliance controlled release, providing a desired deflvery profile over an extended period with rapid onset of efficacious plasma dmg levels and in some cases reduced side effects and a transport rate relatively independent of skin type or site. Additional benefits include easy inception and discontinuation of treatment, patterned and feedback-controlled deflvery, and avoidance of first-pass hepatic metaboHsm. 

Like other xenobiotics, cannabinoids also undergo extensive metabolism in the human body to increase their hydrophihc properties for a facihtated ehmination. The metaboHsm of A9-THC has been very well investigated. More than 100 metabolites of A9-THC are known [99] and a good overview of the most important human metaboHtes is given in [100]. MetaboHsm takes place mainly in hepatic microsomes, but also in intestines, brain. 

Borlakoglu, J.T., J.P.G. Wilkins, M.P. Quick, C.H. Walker, and R.R. Dils. 1991b. Metabohsm of [14C]4-chlorobiphenyl by hepatic microsomes isolated from razorbills, pigeons and rats. Comp. Biochem. Physiol. 99C 287-291. 

The incorporation of in vitro metaboHsm data into allometric seating of compounds cleared by hepatic metabolism has been extensively evaluated [18] and shown to accurately predict human clearance. In this review it is suggested that the utility of such methods are most appropriately applied in drug candidate selection, to confirm early estimates and to support early clinical studies. 

As CHCs and POCs are metabohsed by the liver their use may adversely affect this patient, who has severely compromised liver function. CHC or POC methods should not be advocated in this case. This patient s synthetic and metabohc function is significantly impaired and therefore the metabohsm of CHCs could be affected, precipitating adverse drug reactions such as jaundice, hepatitis and cholestasis. 

Antibiotics, for example rifampicin (SEDA-8, 256), interfere with the hepatic metabohsm of the compounds in oral contraceptives. 

Kharasch ED, Hankins D, Mantz D, Thnmmel KE. Identification of the enzyme responsible for oxidative halothane metabohsm imphcations for prevention of halothane hepatitis. Lancet 1996 347(9012) 1367-71. 

Prescott LF, Critchley JA, Balali-Mood M. Phenylbutazone overdosage abnormal metabohsm associated with hepatic and renal damage. BMJ 1980 281(6248) 1106-7. 

For studies involving metabohsm-mediated effects of xenobiotics, cells that are known to contain the requisite mixed-function oxygenases should be selected. As an alternative, an S9 hepatic microsomal fraction (see Supplementary procedure bioactivation) can be included in the test medium (Borenfreund Puerner, 1987). Serum concentrations should be kept as low as tolerated (or eliminated as in a defined medium) to prevent binding of the test agent to serum components. 

Valproic acid is rapidly and almost completely absorbed after oral administration. Peak concentrations occur 1 to 4 hours after an oral dose. The principal metabolite, 2-n-propyl-3-ketopentanoic acid, is created by action of CyP 2C19 and has anticonvulsant activity comparable to that of valproic acid, although this metabolite does not accumulate in plasma the exact cytochrome enzyme isomer involved in metabohsm has not been identified. The single-dose half-life is 16 hours in healthy adults, but this decreases to 12 hours on chronic therapy and may be as short as 8 hours in children. In neonates and in hepatic disease, when metabolism is reduced, the half-life becomes prolonged. Valproic acid is highly protein bound (93%). In circumstances when competition for protein binding increases, such as in uremia, cirrhosis, or concurrent drug therapy, the percent of free valproic acid increases. 

Following GI absorption or IV administration, benzodk azepines are rapidly distributed to the CNS. Subsequently, benzodiazepines are more slowly redistributed from the CNS to more poorly perfused tissue, such as adipose tissue and muscle. The rate of this redistribution is an important determinant of the duration of action of benzodiazepines and, like that for GI absorption, is largely determined by drug lipophihcity, with the more lipophilic drugs, such as midazolam and triazolam, having the shortest duration of action. Additional factors that influence the duration of benzodiazepine action are hepatic metaboHsm and acute tolerance, resulting in decreased response to benzodiazepines with continued drug exposure. 

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