CLINICAL PHARMACOKINETICS
Pharmacokinetic concepts have been used successfully by pharmacists to individualize patient drug therapy for about a quarter century. Pharmacokinetic consultant services and individual clinicians routinely provide patient-specific drug-dosing recommendations that increase the efficacy and decrease the toxicity of many medications. Laboratories routinely measure patient serum or plasma samples for many drugs, including antibiotics (e.g., aminoglycosides and vancomycin), theophylline, antiepileptics (e.g., phenytoin, carbamazepine, valproic acid, phenobarbital, and ethosuximide), methotrexate, lithium, antiarrhythmics (e.g., lidocaine and digoxin), and immunosuppressants (e.g., cyclosporine and tacrolimus). Combined with a knowledge of the disease states and conditions that influence the disposition of a particular drug, kinetic concepts can be used to modify doses to produce serum drug concentrations that result in desirable pharmacologic effects without unwanted side effects. This narrow range of concentrations within which the pharmacologic response is produced and adverse effects prevented in most patients is defined as the therapeutic range of the drug. Table 8–1 lists the therapeutic ranges for commonly used medications.
Pharmacotherapy: A Pathophysiologic Approach, 8e > Section 1. Foundation Issues > Chapter 8. Clinical Pharmacokinetics and Pharmacodynamics > Clinical Pharmacokinetics and Pharmacodynamics: Introduction >
TABLE 8-1 Selected Therapeutic Ranges
|
|
| Drug | Therapeutic Range |
|---|
| Digoxin | 0.5–2 ng/mL or mg/L |
| 0.6–2.6 nmol/L |
| Lidocaine | 1.5–5 mcg/mL or mg/L |
6.4–21  mol/L |
| Procainamide/N-acetylprocainamide (total) | 10–30 mcg/mL or mg/L (total) |
| 42–127 mol/L |
| Quinidine | 2–5 mcg/mL or mg/L |
| 6–15 mol/L |
Amikacina
| 20–30 mcg/mL or mg/L (peak) |
| 34–51 mol/L (peak) |
| <5 mcg/mL or mg/L (trough) |
| <9 mol/L (trough) |
Gentamicina
| 5–10 mcg/mL or mg/L (peak) |
| 10–21 mol/L (peak) |
| <2 mcg/mL or mg/L (trough) |
| <4 mol/L (trough) |
Tobramycin, Netilmicina
| 5–10 mcg/mL or mg/L (peak) |
| 11–21 mol/L (peak) |
| <2 mcg/mL or mg/L (trough) |
| <4 mol/L (trough) |
| Vancomycin | 20–40 mcg/mL or mg/L (peak) |
| 14–28 mol/L (peak) |
5–15 mcg/mL or mg/L (trough)b
|
3–10 mol/L (trough)b
|
| Chloramphenicol | 10–20 mcg/mL or mg/L |
| 31–62 mol/L |
| Lithium | 0.6–1.4 mEq/L |
| 0.6–1.4 mmol/L |
| Carbamazepine | 4–12 mcg/mL or mg/L |
| 17–51 mol/L |
| Ethosuximide | 40–100 mcg/mL or mg/L |
| 283–708 mol/L |
| Phenobarbital | 15–40 mcg/mL or mg/L |
| 65–172 mol/L |
| Phenytoin | 10–20 mcg/mL or mg/L |
| 40–79 mol/L |
| Primidone | 5–12 mcg/mL or mg/L |
| 23–55 mol/L |
| Valproic acid | 50–100 mcg/mL or mg/L |
| 347–693 mol/L |
| Theophylline | 10–20 mcg/mL or mg/L |
| 56–111 mol/L |
| Cyclosporine (blood) | 150–400 ng/mL or mcg/L |
| 125–333 nmol/L |
|
aUsing a multiple dose per day conventional dosage schedule.
bFor patients with pneumonia or other life-threatening infections, trough concentrations as high as 20 mcg/mL or mg/L (14 mol/L) have been suggested.
Although most individuals experience favorable effects with serum drug concentrations in the therapeutic range, the effects of a given serum concentration can vary widely among individuals. Clinicians should never assume that a serum concentration within the therapeutic range will be safe and effective for every patient. The response to the drug, such as the number of seizures a patient experiences while taking an antiepileptic agent, should always be assessed when serum concentrations are measured.
Throughout this chapter, abbreviations for various pharmacokinetic parameters are used frequently.
Use of Pharmacokinetic Concepts for Individualization of Drug Therapy
 Many factors must be taken into consideration when deciding on the best drug dose for a patient. For example, the age of the patient is important because the dose (in milligrams per kilogram) for pediatric patients may be higher and for geriatric patients may be lower than the typically prescribed dose for young adults. Gender also can be a factor because male and female patients metabolize and eliminate some drugs differently. Patients who are significantly obese or cachectic also may require different drug doses because of clearance and volume of distribution changes. Other drug therapy that could cause drug interactions needs to be considered. Disease states and conditions may alter the drug-dosage regimen for a patient. Three disease states that deserve special mention are CHF, renal disease, and hepatic disease. Renal and hepatic diseases cause loss of organ function and decreased drug elimination and metabolism. CHF causes decreased blood flow to organs that clear the drug from the body.
Many drug compounds are racemic mixtures of stereoisomers. In most cases, one of the isomers is more pharmacologically active than the other isomer, and each isomer may exhibit different pharmacokinetic properties. Warfarin, propranolol, verapamil, and ibuprofen are all racemic mixtures of stereoisomers. Some drug interactions inhibit or increase the elimination of only one stereoisomer. The importance of the drug interaction depends on which isomer is affected. Other drugs, such as dextromethorphan, levofloxacin, and diltiazem, are composed of just one stereoisomer.
 Genetics also plays a role in drug metabolism. Cytochrome P450 is a generic term for the group of enzymes that are responsible for most drug metabolism oxidation reactions. Several cytochrome P450 (CYP) isozymes have been identified that are responsible for the metabolism of many important drugs ( Table 8–3). CYP2C19 is responsible for aromatic hydroxylation of (S)-mephenytoin, and CYP2D6 oxidizes debrisoquine. 15 These subsets of the cytochrome P450 enzyme family are also responsible for the metabolism of several other drugs (CYP2D6: many tricyclic antidepressants, codeine, (S)- metoprolol; CYP2C19: most proton pump inhibitors, sertraline, voriconazole). CYP2C9, CYP2C19, and CYP2D6 isozymes appear to be under genetic control. As a consequence, there are "poor metabolizers" who have a defective mutant gene for the isozyme, cannot manufacture a fully functional isozyme, and therefore cannot metabolize the drug substrate very well. "Extensive metabolizers" have the standard gene for the isozyme and metabolize the drugs normally. Poor metabolizers usually are a minority of the general population. They may achieve toxic concentrations of a drug when usual doses are prescribed for them or, if the active drug moiety is a metabolite, may fail to have any pharmacologic effect from the drug. The ethnic background of the patient can affect the likelihood that the patient will be a poor metabolizer. 15 For example, the incidence of poor metabolizers for CYP2D6 is  5% to 10% for whites and 0% to 1% for Asians, whereas for CYP2C19, poor metabolizers make up 3% to 6% of the white population and 20% of the Asian population. Approximately 7% of the whites are poor metabolizers for CYP2C9 substrates.
Pharmacotherapy: A Pathophysiologic Approach, 8e > Section 1. Foundation Issues > Chapter 8. Clinical Pharmacokinetics and Pharmacodynamics > Clinical Pharmacokinetic Concepts > Use of Pharmacokinetic Concepts for Individualization of Drug Therapy >
TABLE 8-3 Cytochrome P450 Enzyme Family and Selected Substrates
|
|
|
|
|
Other cytochrome P450 isozymes have been isolated. 15 CYP1A2 is the enzyme that is responsible for the demethylation of caffeine and theophylline; CYP2C9 metabolizes phenytoin, tolbutamide, losartan, and ibuprofen; some antiretroviral protease inhibitors, cyclosporine, nifedipine, lovastatin, simvastatin, and atorvastatin are metabolized by CYP3A4; and ethanol is a substrate for CYP2E1. It is important to recognize that a drug may be metabolized by more than one cytochrome P450 isozyme. Although most tricyclic antidepressants are hydroxylated by CYP2D6, N-demethylation probably is mediated by a combination of CYP2C19, CYP1A2, and CYP3A4. Acetaminophen appears to be metabolized by both CYP1A2 and CYP2E1. The 4-hydroxy metabolite of propranolol is produced by CYP2D6, but side chain oxidation of propranolol is probably a product of CYP2C19. The CYP3A enzyme family comprises 90% of the drug-metabolizing enzyme present in the intestinal wall but only 30% of the drug-metabolizing enzyme found in the liver. The remainder of hepatic drug-metabolizing enzyme is 20% for the CYP2C family, 13% for CYP1A2, 7% for CYP2E1, and 2% for CYP2D6.
Understanding which cytochrome P450 isozyme is responsible for the metabolism of a drug is extraordinarily useful in predicting and understanding drug interactions. Some drug-metabolism inhibitors and inducers are highly selective for certain cytochrome P450 isozymes. 15 Quinidine is an extremely potent inhibitor of the CYP2D6 enzyme system; 15 a single 50 mg dose of quinidine can change a rapid metabolizer of debrisoquine into a poor metabolizer. Ciprofloxacin and zileuton inhibit, whereas tobacco and marijuana smoke induces, CYP1A2. Some drugs that are enzyme inhibitors are also substrates for that same enzyme system and appear to cause drug interactions by being a competitive inhibitor. For example, erythromycin is both a substrate for and an inhibitor of CYP3A4. Obviously, if one knows that a new drug is metabolized by a given cytochrome P450 enzyme system, it is logical to assume that the new drug will exhibit drug interactions with the known inducers and inhibitors of that cytochrome P450 isozyme.
 The importance of transport proteins in drug bioavailability and elimination is now better understood. A principal transport protein involved in the movement of drugs across biologic membranes is P-gp. P-gp is present in many organs, including the GI tract, liver, and kidney. If a drug is a substrate for P-gp, its oral absorption may be decreased when P-gp transports drug molecules that have been absorbed back into the GI tract lumen. In the liver, some drugs are transported by P-gp from the blood into the bile, where the drug is eliminated by biliary secretion. Similarly, some drugs eliminated by the kidney are transported from the blood into the urine by P-gp. Digoxin is a substrate of P-gp. Other possible mechanisms for drug interactions are when two drugs that are substrates for P-gp compete for transport by the protein and when a drug is an inhibitor or inducer of P-gp. Drug interactions involving inhibition of P-gp decrease drug transportation in these organs and potentially can increase GI absorption of an orally administered drug, decrease biliary secretion of the drug, or decrease renal elimination of drug molecules. The drug interaction between amiodarone and digoxin probably involves all three of these mechanisms; this explains why digoxin concentrations increase so dramatically in patients receiving amiodarone. Many drugs that are metabolized by CYP3A4 are also substrates for P-gp, and some of the drug interactions attributed to inhibition of CYP3A4 may be a result of decreased drug transportation by P-gp. Drug interactions involving induction of P-gp have the opposite effect in these organs and may decrease GI absorption of an orally administered drug, increase biliary secretion of the drug, or increase renal elimination of drug molecules
|
|
|
|
Comments
Post a Comment