Hepatic clearance of drugs from the bloodstream is influenced by blood flow to the liver, the liver's intrinsic ability to metabolize and remove drugs, and the degree to which drugs are bound to plasma proteins. Blood enters the liver through the hepatic portal vein and hepatic artery, and leaves through the hepatic vein. The liver actively transports some drugs into bile through separate systems for weak acids and bases. These biliary excreted drugs may undergo enterohepatic recirculation by being reabsorbed in the intestines. Many orally administered drugs undergo first-pass metabolism in the liver or intestines before reaching systemic circulation, resulting in lower bioavailability compared to intravenous administration.

1. b.Blood flow, intrinsic clearance, and protein binding affect hepatic clearance.
Blood flow to the liver is approximately 1.5 L/min and may be altered by exercise,
food, disease, or drugs.
Blood enters the liver through the hepatic portal vein and hepatic artery and leaves
through the hepatic vein.
After oral drug administration, the drug is absorbed from the gastrointestinal tract
into the mesenteric vessels and proceeds to the hepatic portal vein, liver, and systemic
circulation.
(2) Intrinsic clearance describes the ability of the liver to remove the drug
independently of blood flow.
Intrinsic drug clearance primarily occurs because of the inherent ability of the
biotransformation enzymes (mixed- function oxidases) to metabolize the drug as it
enters the liver.
Normally, basal level mixed-function oxidase enzymes biotransform drugs. Levels of
these enzymes are increased by various drugs (e.g., phenobarbital) and environmental
agents (e.g., tobacco smoke). These enzymes are inhibited by other drugs and
environmental agents (e.g., cimetidine, acute lead poisoning).

2. (3) Protein binding.
Drugs that are bound to protein are not easily cleared by the liver or kidney because
only the free, or nonplasma protein-bound, drug crosses the cell membrane into the
tissue.
The free drug is available to drug-metabolizing enzymes for biotransformation.
A sudden increase in free-drug plasma concentration results in more available drug at
pharmacologic receptors, producing a more intense effect in the organs (e.g., kidney,
liver) involved in drug removal.
c. Biliary drug excretion, an active transport process, is also included in hepatic
clearance. Separate active secretion systems exist for weak acids and weak bases.
(1) Drugs that are excreted in bile are usually high-molecular- weight compounds (i.e.,
mol wt more than 500) or polar drugs, such as reserpine, digoxin, and various
glucuronide conjugates.
(2) Drugs may be recycled by the enterohepatic circulation.
Some drugs are absorbed from the gastrointestinal tract through the mesenteric and
hepatic portal veins, proceeding to the liver. The liver may secrete some of the drug
(unchanged or as a glucuronide metabolite) into the bile.
From the bile (stored in the gallbladder), the drug may empty into the gastrointestinal
tract through the bile duct.
If the drug is a glucuronide metabolite, bacteria in the gastrointestinal tract may
hydrolyze the glucuronide moiety, allowing the released drug to be reabsorbed.

3. d. First-pass effects (presystemic elimination)
occur with drugs given orally. A portion of the drug is eliminated
before systemic absorption occurs.
(1) First-pass effects generally result from rapid drug biotransformation
by liver enzymes. Other mechanisms include metabolism of the drug
by gastrointestinal mu- cosal cells, intestinal flora, or biliary secretion.
(2) First-pass effects are usually observed by measuring the absolute
bioavailability (F) of the drug. If F is less than 1, then some of the drug
was eliminated before systemic absorption occurred.
(3) (Drugs that have a high hepatic extraction ratio, such as propranolol,
show first-pass effects.
(4) ) If the first-pass effect is high (i.e., more than 90%), then either:
The drug dose could be increased (e.g., propranolol, penicillin).
The drug could be given by an alternate route of administration (e.g.,
nitroglycerin, insulin).
The dosage form could be modified (e.g., mesalamine).