A 57-year-old Caucasian male with severe pyelonephritis is admitted to the hospital. His past medical history is significant for diabetes, hypertension, and two episodes of transient ischemic attacks. His serum creatinine level is 3.2 mg/dL; therefore, he needs to be started on an antibiotic that depends mainly on non-renal clearance. Which of the following characteristics should the antibiotic also have if hepatic metabolism and clearance is desired?

Question

A 57-year-old Caucasian male with severe pyelonephritis is admitted to the hospital.  His past medical history is significant for diabetes, hypertension, and two episodes of transient ischemic attacks.  His serum creatinine level is 3.2 mg/dL; therefore, he needs to be started on an antibiotic that depends mainly on non-renal clearance.  Which of the following characteristics should the antibiotic also have if hepatic metabolism and clearance is desired?

Quizplus · Accepted Answer

The kidney is the primary site of excretion of most drugs, with or without prior chemical modification in the liver. The liver is the major site of drug biotransformation and metabolism, but some drugs are also predominately eliminated by the liver into the bile and feces. Drugs with high intrinsic hepatic clearance tend to have high lipophilicity and a high volume of distribution. Highly lipophilic drugs tend to be poorly eliminated in the kidney as these agents rapidly cross tubular cell membranes after filtration to reenter the tissues. High lipophilicity (lipid solubility) allows the drug to cross cellular barriers more easily and enter hepatocytes. It can then be excreted in the bile or through other methods of elimination. In addition, high lipid solubility assures a wide distribution to many different tissues including the brain, liver, and adipose tissue. (Choice A) Drugs with a low distribution volume tend to be confined to the bloodstream and tend not to diffuse readily through hepatocytes into the bile. Thus, a drug with a low V_d will be highly plasma protein-bound and hydrophilic, making it less available for hepatic metabolism and more readily available for excretion unchanged in the urine. (Choice B) A drug that is not well absorbed orally may have a high pre-systemic (first-pass) elimination or be poorly lipid-soluble. In both cases, it will be unavailable to the liver for hepatic clearance. (Choice D) A low rate of redistribution from one compartment to another implies low lipid solubility or significant hydrophilicity. These drugs tend to remain in the intravascular compartment and be eliminated by the kidneys. (Choice E) Poor central nervous system penetration indicates that a drug is likely not lipophilic, and therefore has a low volume of distribution. It is therefore also unlikely that the same drug will be eliminated in large amounts by the liver. Educational Objective: While the kidney is the primary site of elimination of most drugs, the liver is the main site of biotransformation of these agents in preparation for elimination. Drugs that are more lipophilic (high V_d, good penetration into CNS) are preferentially processed by the liver into more polar compounds for easier elimination in the bile and urine. Liver disease (e.g., cirrhosis) or the concomitant use of other drugs may limit or enhance the clearance of drugs metabolized in the liver.

A 57-Year-Old Caucasian Male with Severe Pyelonephritis Is Admitted to the Hospital