Ketamine is a medication recognized for its dual roles as an anesthetic and a therapeutic agent, particularly in treating certain mental health conditions. Its unique properties stem from its ability to induce a dissociative state, separating the mind from sensory input. Understanding how the body processes ketamine helps explain its rapid onset and varied effects.
Ketamine’s Journey into the Body
Ketamine can enter the bloodstream through various routes, including intravenous (IV), intramuscular (IM), oral, and nasal administration. Intravenous administration provides nearly 100% bioavailability, leading to a rapid onset of action. Intramuscular injection also offers high bioavailability, around 93%, with peak plasma levels typically reached within 5 to 30 minutes.
Oral administration results in significantly lower bioavailability, approximately 17% to 29%, because a substantial portion is metabolized in the liver before entering general circulation. Nasal spray administration generally offers higher bioavailability than oral routes, ranging from 25% to 50%. Once absorbed, ketamine quickly distributes throughout the body, particularly to highly perfused organs such as the brain, liver, and kidneys.
The Primary Metabolic Pathway
The liver is the main site for ketamine metabolism, largely carried out by cytochrome P450 (CYP) enzymes. CYP3A4 is the dominant enzyme responsible for the initial breakdown of ketamine.
The primary metabolic step is N-demethylation, which converts ketamine into its major active metabolite, norketamine. While CYP3A4 plays a major role, CYP2B6 and CYP2C9 also contribute to this process. Norketamine retains some of ketamine’s pharmacological activity, including anesthetic and psychoactive properties, though it is generally less potent.
Norketamine’s half-life is typically longer than ketamine’s, ranging from approximately 2 to 3 hours, which contributes to sustained effects after administration.
Further Breakdown and Excretion
Following its formation, norketamine undergoes further metabolism through processes like hydroxylation. This involves the addition of hydroxyl groups to the norketamine molecule, leading to the formation of various hydroxynorketamine derivatives. Among these, (6)-hydroxynorketamine (HNK) is frequently detected as a significant circulating metabolite in human plasma.
These hydroxylated metabolites, including hydroxynorketamine, are then primarily made more water-soluble through a process called glucuronidation. Glucuronidation involves attaching glucuronic acid molecules to the metabolites, which facilitates their elimination from the body. These inactive, water-soluble compounds are then predominantly removed by the kidneys and excreted in the urine.
The majority of ketamine and its metabolites, roughly 85-95% of the administered dose, are eliminated through urine. Only a small percentage, about 2-4%, of the original ketamine drug is excreted unchanged. Norketamine itself accounts for approximately 2% of the excreted amount, while dehydronorketamine accounts for about 16%. The largest portion, around 80%, is excreted as conjugates of hydroxylated ketamine metabolites with glucuronic acid.
Factors Affecting Ketamine Metabolism
Several factors can influence the rate and extent of ketamine metabolism, leading to variations in its effects among individuals. Genetic variations in the activity of CYP enzymes, particularly CYP2B6 and CYP3A4, can significantly alter how quickly ketamine is processed. The CYP2B66 allele, for instance, is associated with reduced ketamine metabolism, which can lead to higher plasma concentrations of the drug.
Age also plays a role in ketamine metabolism. Children tend to metabolize ketamine more rapidly than adults, potentially requiring higher doses to achieve desired effects. Conversely, older patients may metabolize the drug more slowly, necessitating lower doses. This age-related difference is possibly due to changes in liver volume, hepatic blood flow, and the overall content and function of CYP enzymes like CYP2B6 and CYP3A4 in older individuals.
Liver function is another important determinant; impaired liver function can slow down ketamine metabolism, potentially prolonging its effects and increasing the risk of accumulation. Drug-drug interactions can also occur when other substances inhibit or induce the activity of CYP enzymes. Certain medications, for example, can inhibit CYP450 enzymes, leading to increased levels of ketamine and norketamine in the body while reducing the formation of hydroxynorketamines.