Hepatic first-pass effect

Whether given orally or parenterally, drugs are distributed nonuniformly throughout the body. Factors that regulate this distribution are the lipophilic characteristics of the drugs, the blood supply to the tissues, and the chemical composition of various organs and tissues. The distribution 

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The fraction of the orally administered dose that is bioavailable to the systemic circulation (Fsystemjc) is dependent upon the fraction of the dose that is released from the dosage form (/released), multiplied by the fraction that is absorbed into the portal circulation on its way to the liver (/absorbed this is the fraction that escapes gut metabolism), multiplied by the fraction of the dose that escapes the hepatic first-pass effect (/hepatic)- Since this is a multiplicative process if, for... 

Lee YH, Perry BA, Lee HS, Kunta JR, Sutyak JP and Sinko PJ (2001) Differentiation of Gut and Hepatic First-Pass Effect of Drugs 1. Studies of Verapamil in Ported Dogs. Pharm Res 18 pp 1721-1728. 

Noticeably propranolol, betaxolol and metoprolol are close or on the borderline for hepatic first-pass effects, whereas talinolol falls markedly below it. Talinolol has been shown to be a substrate for P-glycoprotein [14]. The effect of the urea function is of key importance within this change, as urea lacks a strong type I unit in terms of Seel-... 

A brief review of pharmacokinetic principles will place the available data on gender differences in context. Bioavailability, which refers to the amount of drug eventually reaching the systemic circulation, is influenced by absorption, metabolism in the gastrointestinal tract, and the hepatic first-pass effect. The impact of the first-pass effect is greater for drugs that have high hepatic... 

After the drug is absorbed, it may be taken up by hepatocytes and metabolized, a process that is referred to as the hepatic first-pass effect. If the compound is highly extractable, then the amount of drug removed is high and the degree of available drug is lowered. It is not known whether there are gender differences in hepatic blood flow that can influence the extraction rate of some medications. 

This agent has a broad spectrum of activity encompassing several neurotransmitter systems. In this light, clozapine is similar to such phenothiazines as CPZ and thioridazine (519). It is also subject to a hepatic first-pass effect, which produces metabolites with low or unknown pharmacological activity. It has an elimination half-life ranging from 6 to 33 hours and a volume of distribution (V 5 l /kg) lower than most other antipsychotics. This last quality indicates less drug is sequestered in tissue sites. Plasma levels of the parent compound at or above 350 ng/mL may be associated with a better clinical response ( 66, 520). Plasma levels are lower in men than women, especially male smokers (329). 

First-Pass Effect Biotransfonnation of a xenobiotic before it reaches the systemic circulation. The biotransformation of an intestinally absorbed xenobiotic by the liver is referred to as a hepatic first-pass effect. 

The hepatic first-pass effect can be avoided to a great extent by use of sublingual tablets and transdermal preparations and to a lesser extent by use of rectal suppositories. Sublingual absorption provides direct access to systemic—not portal—veins. The transdermal route offers the same advantage. Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead to the liver predominate. Thus, only about 50% of a rectal dose can be assumed to bypass the liver. 

Although drugs administered by inhalation bypass the hepatic first-pass effect, the lung may also serve as a site of first-pass loss by excretion and possibly metabolism for drugs administered by nongastrointestinal ("parenteral") routes. 

The olfactory region located in the poorly accessible recessed roof of the nasal passages offers the potential for certain compounds to circumvent the blood-brain barrier and enter into the brain [48]. The olfactory sensory cells are in contact with both the nasal cavity and the CNS and this neuronal connection constitutes a direct pathway to the brain. By utilizing this pathway drugs would not only circumvent the blood-brain barrier, but also avoid any hepatic first-pass effect and degradation in the blood compartment, a particularly important issue in the case of peptide drugs. 

Transdermal estradiol is indicated for postmenopausal hormone replacement therapy. Estradiol is a potent, high clearance (600- 800 L/hr) and short half-life (1 hr) dmg. Due to the very high hepatic first-pass effect, conventional oral hormone replacement therapy results in an artificially elevated and, in the long... 

Isradipine (Fig. 7.5) is a further nifedipine analogue, which has been used in the treatment of hypertension either alone or in combination with diuretics. Isradipine possesses high calcium antagonist activity, which results in a peripheral vasodilatation without any detrimental effect on cardiac conduction. Its oral bioavailability is 90-95% of the administered dose, but the hepatic first-pass effect reduces this to 15-24%. Isradipine was shown to possess anti-atherosclerotic activity in a number of experimental models, but clinical studies (MIDAS) failed to confirm these findings in patients. 

Nisoldipine (Fig. 7.7) is an analogue of nifedipine, but it is at least five to ten times more potent than nifedipine on arterial smooth muscle, without affecting myocardial contractility. It also possesses a very potent and selective relaxation activity on small arteries, and therefore it can be used for the treatment of hypertension. Since its duration is limited by a massive hepatic first-pass effect, it is currently used as an extended-release formulation for once-daily administration. 

The inhalation route of exposure is preferred. When the endpoint of concern is systemic toxicity and the hepatic first-pass effect is not significant, oral exposure may be considered. In the absence of scientifically sound inhalation data and with high confidence in a valid route-to-route extrapolation, routes of exposure other than inhalation will not be used for AEGL derivation. 

Pharmacokinetics PTU is rapidly absorbed. The oral bioavailabi% of 50% to 80% may be due to a large hepatic first-pass effect. Methimazole is completely absorbed. The duration of action for PTU is approximately 7 hours and therefore requires multiple daily doses (every 6 to 8 hours). 

Absorption from the rectum depends on various physiological factors such as surface area, blood supply, pH, fluid volume, and possible metabolism by microorganisms in the rectum. The rectum is perfused by the inferior and middle rectal arteries, whereas the superior, the middle, and the inferior rectal veins drain the rectum. The latter two are directly connected to the systemic circulation the superior rectal vein drains into the portal system. Drugs absorbed from the lower rectum are carried directly into the systemic circulation, whereas drugs absorbed from the upper rectum are subjected to hepatic first-pass effect. Therefore, a high-clearance drug should be more bioavailable after rectal than oral administration. The volume of fluid in the rectum, the pH of that fluid, and the presence of stool in the rectal vault may affect drug absorption. Because the fluid volume is... 

The half-life is a useful kinetic parameter for therapeutic molecules, as it defines the dosing interval at which drugs should be administered. Half-life also describes the time required to reach steady state, or to decay from steady-state conditions after a change in the administration regimen. However, as an indicator of the processes involved in drug elimination or distribution the half-life has only limited value. It must be mentioned that, for many proteins and peptides, the glomerular filtration rate is high, and has more impact on the elimination of a biopharmaceutical than does the hepatic first-pass effect [7]. 

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