Pharmacokinetics: Biotransformation

Biotransformation

Biotransformation is the chemical process by which the drug molecule is altered in thebody. The liver is the primary organ of metabolism for drugs. The exception is esters, which undergo hydrolysis in the plasma or tissues. The end products of biotransformation are often (but not necessarily) inactive and water soluble. Water solubility allows excretion by the kidneys.

Metabolic biotransformation is frequently divided into phase I and phase II reactions. Phase I reactions convert a parent compound into more polar metabolites through oxidation, reduction, or hydrolysis. Phase II reactions couple (conjugate) a parent drug or a phase I metabolite with an endog-enous substrate (eg, glucuronic acid) to form water-soluble metabolites that can be eliminated in the urine or stool. Although this is usually a sequential process, phase I metabolites may be excreted with-out undergoing phase II biotransformation, and a phase II reaction can precede or occur without a phase I reaction.Hepatic clearance is the volume of blood or plasma (whichever was measured in the assay) cleared of drug per unit of time. The units of clearance are units of flow: volume per unit time. Clearance may be expressed in milliliters per minute, liters per hour, or any other convenient unit of flow.

If every molecule of drug that enters the liver is metabolized, then hepatic clearance will equal liver blood flow. This is true for very few drugs, although it is very nearly the case for propofol. For most drugs, only a fraction of the drug that enters the liver is removed. The fraction removed is called the extraction ratio. The hepatic clearance can there-fore be expressed as the liver blood flow times the extraction ratio. If the extraction ratio is 50%, then hepatic clearance is 50% of liver blood flow. The clearance of drugs efficiently removed by the liver (ie, having a high hepatic extraction ratio) is propor-tional to hepatic blood flow. For example, because the liver removes almost all of the propofol that goes through it, if the hepatic blood flow doubles, then the clearance of propofol doubles. Induction of liver enzymes has no effect on propofol clear-ance, because the liver so efficiently removes all of the propofol that goes through it. Even severe loss of liver tissue, as occurs in cirrhosis, has little effect on propofol clearance. Drugs such as propofol have flow-dependent clearance.

Many drugs have low hepatic extraction ratios and are slowly cleared by the liver. For these drugs, the rate-limiting step is not the flow of blood to the liver, but rather the metabolic capacity of the liver itself. Changes in liver blood flow have little effect on the clearance of such drugs. However, if liver enzymes are induced, then clearance will increase because the liver has more capacity to metabolize the drug. Conversely, if the liver is damaged, then less capacity is available for metabolism and clear-ance is reduced. Drugs with low hepatic extraction ratios thus have capacity-dependent clearance. The extraction ratios of methadone and alfentanil are 10% and 15% respectively, making these capacity-dependent drugs.