Most drugs, after journeying through the various metabolic systems throughout the body, find their exit.
Editor in Chief
A mythology exists that creates one of the most significant nemeses for the practicing clinician in psychiatry: drug formularies that impose drug dosage and dispensing limitations that quite often result in an unnecessary and burdensome obstacle to our goal of effectively treating patients. Many of us older psychiatric clinicians reminisce back to a time absent of drug formularies when we could dose a medication unencumbered to maximize the benefit to our patient. Sadly, we have surrendered our power to the insurance magnates who pretend to be more knowledgeable than we are about the medication choices and doses that will provide the best treatment-and hence outcome-for our patients.
A medication’s dosage used in phase 3 clinical trials is chosen to create the highest likelihood of clinically significant separation from placebo, while minimizing adverse effects. Additionally, as required by the FDA to create as clean a treatment population as is possible, participants in clinical trials are not illustrative of the patients we treat on a day-to-day basis in our clinical practices. For most phase 3 clinical trials, subjects can have no psychiatric comorbidity, no significant medical problems, no recent or active substance use disorder, and no serious acute symptoms. They cannot be pregnant, must be of a specific age range, and must be competent to understand and consent to the treatment protocol-and this is just the short list. The enrollment requirements would exclude more than 90% of the patients that I have treated at Seacoast Mental Health Center, where I have practiced for the past 12 years.
It is only after a medication is FDA approved, and we prescribe it to hundreds of thousands of patients-all with unique factors that will determine a serum drug level for each individual patient-that we learn the true clinical range of a new drug. Two common examples of this are risperidone, which we initially dosed too high (based on the FDA approved initial product insert), and ziprasidone, which we initially dosed too low (based on the FDA approved initial product insert). In a time when cost savings is the driving force behind insurance company policies, it would seem wise and prudent to allow treating clinicians to choose the medication they deem most appropriate for a specific patient, and dose it as aggressively as is clinically indicated to improve the patient’s symptoms and functioning and minimize toxicity to the brain.
Let us look at the many variables, unique to each patient, that influence a medication’s serum level. In clinical reality, it is the serum level of the drug, and not the dose of the drug, that determines clinical response. So, let us follow the journey of a drug from the pill bottle to the toilet.
Getting the medication into the body
The first step in the process of getting a clinically effective drug level is getting it into the body. The best route of administration is determined by the many pharmacokinetic and pharmacodynamic properties of the drug. The most common delivery system is that of oral administration, where the medication is simply swallowed. Even with this route of administration significant rules may apply to obtain consistent and adequate serum levels. One common example is that of levothyroxine, which needs to be taken on an empty stomach. Other drugs may require the presence of a specific number of calories to maximize absorption, or a specific pH of the stomach.
Other drugs are best administered sublingually. This route of administration in some cases is required. The classic case in psychiatry is asena- pine, which is primarily metabolized by a phase 2 enzyme that is highly prevalent in the gut. If asenapine is swallowed, up to 99% of it is transformed into an inactive metabolite by UGT (uridine 5-diphosphate glucuronosyltransferase) 1A4 (family = 1, subfamily = A, gene = 4). To maximize sublingual absorption, the tablet is kept under the tongue for 10 minutes, and ideally no swallowing occurs during this time.
In most cases, the fastest way to get a drug into the body is through intravenous injection, which usually results in the highest bioavailability of the dose. A close second is administration through intramuscular injection and subcutaneous injection. These two routes of administration are often used to inject drugs available in a long-acting delivery system that can allow for weekly, monthly, bi-monthly, and even tri-monthly administration.
Another route of absorption shown to have advantages for various clinical and pharmacological reasons is transdermal administration, whereby a transdermal matrix/patch is adhered to the skin that releases the drug. Examples include selegiline, nicotine, rivastigmine, buprenorphine, and methylphenidate. Additional delivery systems include intranasal spray and nebulizer inhaler.
Absorption from the gastrointestinal tract
Early in drug development, it is determined what the best route of administration is for a specific drug. Some drugs have multiple routes of administration, which provides a broader range of options to better suit clinical variables. Currently, oral drug administration remains the most common route, and creates a wide range of absorption variables that can significantly affect how much or how little drug actually makes it into the body’s circulation.
The first challenge is keeping the drug intact as it moves through the stomach. Variables include the pH of the stomach, the rate of gastric emptying, and in some cases, drug absorption by the stomach. If a patient has had gastric surgery, including gastric bypass/stapling/lap band placement, the result can be a “dumping” syndrome where the drug’s visit in the stomach is all too brief. When I have a patient scheduled for gastric bypass surgery, I check a 12-hour post-dose serum level of all of the drugs that I prescribe to get a baseline serum level before the mechanics of the stomach are forever altered. One month post-gastric bypass I repeat these drug levels, which allows me to adjust the dose to re-create the serum level the patient had been previously stable on.
Once passage through the stomach is complete, next is the long and winding road through the small and large intestines. Many of the body’s drug metabolizing systems exist in the intestines, as well as the liver and other organ systems. Three primary drug metabolic processes are already at work at the lining of the gut: P-glycoprotein activity, phase 1 cytochrome P-450 metabolism, and phase 2 conjugation. This makes sense, as the site of absorption by the gastrointestinal (GI) tract is the perfect location for a first-line defense against potentially toxic molecules. P-glycoproteins serve to pump back out into the gut lumen potentially dangerous molecules, and phase 1 and phase 2 metabolism serve to inactivate through enzymatic drug modification any potentially toxic molecules ingested by the local food sources.
Transit time through the intestine can dramatically alter drug absorption. A patient with irritable bowel syndrome with rapid transit time may see an intact medication tablet or capsule mixed in with his or her stool. This can be more common with an extended-release delivery system. Certain food products, or other medications may bind to a drug and carry it further down the GI tract where absorption is poorer.
As many will remember from anatomy class, the superior and inferior mesenteric veins, which carry all substance absorbed by the intestines, merge with the splenic vein to form the portal vein, which then filters its content through that great metabolic factory-the liver. This first-pass metabolism process provides the metabolic pathways to modify drug structures to be more water soluble, so they can eventually leave the body through renal excretion, or in other cases adds various structures to enhance passage out with the bile. There are two primary types of metabolic pathways1:
PHASE 1 cytochrome P-450 (CYP450) enzyme metabolism. In humans, there are approximately 60 CYP450 enzymes, which are differentiated by the nomenclature of family (Arabic numeral), sub-family (uppercase letter), and gene (Arabic numeral). The best studied CYP450 enzyme is CYP450 2D6, which itself has many genetic polymorphisms. These polymorphisms create a wide range of phenotypic functionality for CYP450 2D6 (poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer), which results in a wide range of drug serum levels in individuals who appear identical by all other measures.
The CYP450 enzymes can be significantly turned on or off by drug-drug interactions, further complicating the picture. At each CYP450 enzyme, a drug can be a substrate, inducer, or inhibitor. In psychiatry, many antidepressants and antipsychotics are metabolized by CYP2D6, and it is one of only four genes that have been deemed clinically actionable by both the Clinical Pharmacogenetics Implementation Consortium and the International Society of Psychiatric Genetics.
PHASE 2 conjugation metabolism. Although as important as phase 1 metabolism, phase 2 metabolism is much less understood. It involves adding a water-soluble molecule to a drug. These reactions result in strong covalent bonds of the drug with amino acids, sulfate, glucuronic acid, and other molecules. Common examples of phase 2 metabolism of psychiatric drugs include divalproate, lamotrigine, asenapine, and lorazepam. Like CYP450 enzymes, there is a wide range of genetically determined functional activity for each of these enzymes as well as drugs that can induce and inhibit them.
Phase 1 and phase 2 metabolism can occur in other organ systems. CYP450 and UGTs are common in the gut. Recent studies have demonstrated that the brain contains microenvironments where activity of CYP450 enzymes are different than in the liver.2 This suggests that cerebrospinal fluid (CSF) levels can differ from serum levels of the same drugs.
Variability in the brain
Our job as psychopharmacologists would be too easy if the concentration of a drug in the CSF were the same as the serum drug level. But, of course, this is not at all the case. As mentioned above, metabolic enzyme activity in the brain can differ from the same pathways in the rest of the body. Moreover, each drug has its own unique rules as to how it crosses the blood-brain barrier.
One property is that of lipophilicity. The more fat soluble a drug is, the easier it is for it to slide across the blood-brain barrier; however, some of these drugs are then pumped out of the brain through adenosine triphosphate (ATP)-driven transport pumps. These pumps, called P-glycoproteins (P for permeability), are well established transport pumps that are found in many organs throughout the body. The blood-brain barrier’s endothelial cells contain a large population of diverse P-glycoproteins that, like the phase 1 and phase 2 metabolic enzymes, have significant genetic variability, as well as being subject to induction and inhibition by other drugs.
Although still in its infancy, pharmacogenomics is demonstrating that genetic variability of specific genes for neurotransmitter receptors and transport pumps can make a specific drug either more or less potent at its target in the brain.
Other variables affecting drug serum levels
Well-established mechanisms can vary among individuals or within a single person over time, which can impact the serum level of a drug. These include: protein binding, cardiac output, degree of hydration, amount of adipose tissue, body mass index, muscle mass, comorbid medical conditions, co-prescribed medications, substance use and/or abuse, daily inhalation of smoke from any source, and age of the patient.
Exiting the body
For a drug to complete its journey to the toilet, it needs to leave the body. Most drugs, after journeying through the various metabolic systems throughout the body, find their way into urine through renal excretion. Hence, renal impairment-temporary, permanent, mild, or progressive-will have a direct impact on the drug’s half-life, hence affecting steady-state blood levels. Other exit pathways for drugs include: biliary excretion, GI non-absorption, sweating it out, breathing it out, and hemodialysis.
So, there you have it-the drug’s journey. There are so many numerous unique and unpredictable variables that will determine the dosage of a medication required to achieve the optimal serum drug level for our patients. Thus, it is comical that drug formularies have established fire walls to limit our prescribing decisions.
Dear Medicaid, Medicare, and Insurance Company drug formularies:
Please allow me to prescribe the medication that, based on my extensive education and clinical experience, I deem clinically appropriate for my patient that you have never met or evaluated. Additionally, please do not obstruct my clinical dosing decisions for my patient, which I based upon my assessment of all the factors discussed above. You might be pleasantly surprised by the subsequent cost savings: improved patient symptoms, improved patient functioning, decreased hospital stays, decreased emergency room visits, decreased polypharmacy, improved long-term functioning with improved vocational engagement and social functioning, and a healthier population of individuals to pay your insurance premiums.
Well, just thought I would ask!
1. Cozza KL, Armstrong SC, Oesterheld JR. Drug Interaction Principles for Medical Practice. Washington, DC: American Psychiatric Publishing; 2003.
2. Toselli F, Dodd PR, Gillam EMJ. Emerging roles for brain drug-metabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs. Drug Metabol Rev. 2016;48:379-404.