Pharmacokinetics and Serum Drug Concentrations

When a drug is given orally, it undergoes several steps in the body and its concentration in serum or whole blood is affected by certain steps.

1. Liberation: The release of a drug from the dosage form (tablet, capsule, extended release formulation)

2. Absorption: Movement of drug from site of administration (for drugs taken orally) to blood circulation

3. Distribution: Movement of a drug from the blood circulation to tissues. This distribution in most cases is reversible. Certain drugs also cross the blood brain barrier.

4. Metabolism: Chemical transformation of a drug to the active and inactive metabolites. Cytochrome P450 enzyme system is the major drug-metabolizing agent of body.

5. Excretion: Elimination of the drug from the body through renal, biliary, or pulmonary mechanism.

Liberation of a drug after oral administration depends on the formulation of the dosage. Immediate release formulation releases the drugs at once from the dosage form when administered. On the contrary, the same drug may also be available in sustained release formulation. The rationales for specialized oral formulations of drugs include prolongation of the effect for increased patient convenience and reduction of adverse effects through lower peak plasma concentrations. Local and systematic adverse effects of a drug can also be reduced by use of controlled release delivery systems (8). Over the past decade, there has been a significant growth in the introduction of these new formulations of existing drugs designed to improve patient management (9). Controlled release dosage formulations include osmotic pumps and zero-order kinetics system to control the release rate of a drug, bio-adhesive systems and gastric retention devices to control gastrointestinal transit of a drug, bio-erodible hydrogels; molecular carrier system such as cyclodextrin-encapsuled drugs; externally activated system; and colloidal systems such as liposomes and microspheres (8). The effect of food intake on bioavailability of a drug is more apparent on a single unit non-disintegrating dosage form, although controlled release formulations are not completely immune from the food intake. Polymers occupy a major portion of materials used for controlled release formulations and drug-targeting systems because this class of substances presents seemingly endless diversity in chemistry and topology (10). Microparticles are small solid particulate carriers containing dispersed drug particles either in solution or in crystalline form. The importance of microparticles is growing because of their utilization as carriers for drugs and other therapeutic agents. Microparticles are made from natural or synthetic polymers. Different materials have been used for microparticles systems, such as albumin, gelatin, starch, ethyl cellulose, and synthetic polymers, such as poly lactic acid, poly cyanoacrylates, and poly hydroxy-butyrate (11). Enteric coded formulations resist gastric acid degradation and deliver drugs into the distal small intestine and proximal colon. Budesonide, a synthetic gluco-corticoid with high topical anti-inflammatory activity and little or no systemic effect, has been administered through inhalation for the treatment of inflammatory airways infection. Budesonide is also manufactured into two commercially available oral control release formulations, and both the formulations are enteric coded (12). Recently, enteric coded formulation of mycophenolic acid mofetil, a prodrug of immunosuppressant mycophenolic acid is commercially available (13). Solid nanoparticles were introduced in the 1990s as an alternative to microemulsions, polymeric nanoparticles, and liposomes. These nanoparticles have several advantages such as biocompatibility and their capability of controlled and targeted drug release (14).

Oral controlled release drug delivery systems can be further classified into two broad categories; single-unit dosage forms (SUDFs) such as tablets or capsules and multiple-unit dosage forms (MUDFs) such as granules, pellets, or mini-tablets. Mini-tablets are tablets with a diameter equal to or smaller than 2-3 mm (15). Several mini-tablets can be either filled into hard capsules or compacted to a bigger tablet that after disintegration releases these subunits as multiple dosage form. Many drugs are available in sustained release formulations. For example, the immediate release venlafaxine, an antidepressant formulation, requires twice-daily administration whereas the extended release formulation is designed for once-daily administration. Another antidepressant fluoxetine is available in a sustained release dosage form, which requires once-weekly administration for continuation of therapy for depression (16). Calcium channel antagonists are a heterogenous group of drugs with different cardiovascular effects and are effective in the treatment of hypertension and angina pectoris. A number of these agents are commercially available in sustained release formulations (17). Anticonvulsants, such as carbamazepine and valproic acid, are also available in sustained release formulations (18,19). Theophylline is available in prolonged release form (20). Procainamide, a class IA antiarrhythmic drug, is also administered as sustained release formulation (21). McCormack and Keating (22) recently reviewed the use of prolonged release nicotinic acid in treating lipid abnormality.

Absorption of a drug depends on the route of administration as well as drug formulation. Generally, an oral administration is the route of choice in the practice of pharmacotherapy, but under certain circumstances (nausea, vomiting, convulsions etc), rectal route may present a practical alternative for drug administration. Rectal administration is now well accepted for delivering anticonvulsants, non-narcotic and narcotic analgesics, theophylline, and antibacterial and antiemetic agents. This route can also be used for inducing anesthesia in children. The rate and extent of rectal drug absorption are often lower compared with oral absorption possibly because of small surface area available for drug absorption. The composition of rectal formulation (solid vs. liquid, nature of suppository) also plays an important role in the absorption of a drug. However, for certain drugs, rectal absorption is higher compared with absorption of the same drug given orally. This phenomenon may be due to avoidance of the hepatic first-pass metabolism after rectal delivery. These drugs include lidocaine, morphine, metoclo-pramide, ergotamine, and propranolol. Local irritation is a possible complication of rectal drug delivery (23).

When a drug is administered by direct injection, it enters the blood circulation immediately. Sometimes, a drug may be administered by the intravenous or intramuscular route as a prodrug if the parent drug has potential for adverse drug reactions at the injection site. Fosphenytoin is a phosphate ester prodrug of phenytoin developed as an alternative to intravenous phenytoin for acute treatment of seizure. However, the bioavailability of derived phenytoin from fosphenytoin relative to intravenous phenytoin administration is almost 100% (24).

There is considerable interest to deliver a drug through the transdermal route. However, the skin, particularly the stratum corneum, poses a formidable barrier to drug penetration, thus limiting topical and transdermal bioavailability of a drug (25). As early as in 1967, it was demonstrated that the bioavailability of topically applied hydrocortisone alcohol was only 1.7% (26). For a drug to be delivered passively through the skin, it should have adequate lipophilicity and a molecular weight <500 D (27). Penetration enhancement techniques are usually used to improve bioavailability following transdermal delivery of a drug. This enhancement technique is based on drug/vehicle optimization such as drug selection, prodrug and ion pairs, supersaturated drug solutions, eutectic systems, complexation, liposome vesicles, and particles. Enhancement through modification of stratum corneum by hydration, and chemical enhancers acting on the lipids and keratin of stratum corneum are also utilized for transdermal drug delivery (25). Major routes of administration of drugs in a patient and its advantages and disadvantages are summarized in Table 2.

When a drug enters the blood circulation, it is distributed throughout the body to various tissues. The pharmacokinetic term most often used to describe distribution is called volume of distribution (Vd). This is the hypothetical volume to account for all drugs in the body and is also termed as the apparent Vd

Vd = Dose/plasma concentration of drug

The amount of a drug at a specific site, where it exerts its pharmacological activity or toxicity, is usually a very small fraction of the total amount of the drug in the body because of its distribution in tissue and blood. Even in a target tissue, only a fraction of the drug binds with the receptors and exerts its pharmacological activity. Protein binding of a drug also limits its movement into tissues. Muscle and fat tissues may serve

Table 2

Routes of Administration of Drugs and Their Advantages as well as Disadvantages

Table 2

Routes of Administration of Drugs and Their Advantages as well as Disadvantages





Route of choice because of ease of administration

Longer time to peak level; Food, alcohol may affect levels

Sustained release formulation prolonged effect

Gastric-emptying time, First-pass metabolism affect levels


Can be used if patient has nausea, vomiting, convulsion Inducing anesthesia in children Few drugs show higher absorption compared with oral route because of avoidance of first-pass metabolism such as lidocaine

Absorption may be low; Local irritation


Rapid peak concentration and action

Need a intravascular access for administration/discomfort


No first-pass metabolism 100% Bioavailability

Transdermal Sublingual

Ease of application Rapid absorption and action Ease of application

Poor systematic absorption First-pass metabolism

as a reservoir for lipophilic drugs. For central nervous system drugs (neurotherapeutics), penetration of blood brain barrier is essential. Usually, moderately lipophilic drugs can cross the blood brain barrier by passive diffusion, and hydrogen-bonding capacity of a drug can significantly influence the central nervous system uptake. However, drugs may also cross the blood brain barrier by active transport (28). When a CNS drug is given as a prodrug, a delay may be observed in the accumulation of the drug in the brain because of the time required for conversion of the prodrug to the original drug. Walton et al. (29) reported that when fosphenytoin, the prodrug of phenytoin, was administered in rats, lower brain levels of phenytoin were typically observed compared with brain phenytoin levels when phenytoin was directly administered in rats. Many drugs do not effectively penetrate the blood brain barrier. Ningaraj et al. (30) recently commented on challenges in delivering new anticancer drugs to brain tumors because most new anticancer drugs that are effective outside the brain have failed in clinical trials in treating brain tumors, in part because of poor penetration across the blood brain barrier and the blood brain tumor barrier. However, there are also advantages when a drug does not effectively penetrate the blood brain barrier. Second generation antihistamines have a low tendency to cross the blood brain barrier and thus reduce sedation and impairment in patients (31).

Drugs usually undergo chemical transformation before elimination, and the process is termed as metabolism. Drug metabolism may occur in any tissue including the blood. For example, plasma cholinesterase, a glycoprotein synthesized in the liver metabolizes drugs such as cocaine and succinylcholine. Hoffman et al. (32) reported that decreased plasma cholinesterase activity is associated with the increasing risk of life-threatening cocaine toxicity. However, the liver is the main site for drug metabolism. The role of metabolism is to convert lipophilic non-polar molecules to more polar water-soluble compounds for effective excretion in urine. The drug molecule can be modified structurally (oxidation, reduction, or hydrolysis), or the drug may undergo conjugation (glucuronidation, sulfation) that increases its polarity. The rate of enzymatic process that metabolizes most drugs is usually characterized by the Michaelis-Menten equation and follows first-order kinetics (rate of elimination is proportional to drug concentration). However, for certain drugs for example, phenytoin, the metabolism is capacity-limited.

The half-life of a drug is the time required for the serum concentration to be reduced by 50%. The fraction of a drug that remains in the body after five half-lives is approximately 0.03 (Fig. 1). However, after multiple doses, usually a drug reaches a steady state after five to seven half-lives. Half-life of a drug can be calculated from elimination rate constant (K) of a drug.

Elimination rate constant can be easily calculated from the serum concentrations of a drug at two different time points using the formula where Ct1 is the concentration of drug at a time point t1 and Ct2 is the concentration of the same drug at a later time point t2:


Fig. 1. Fraction of drug (given in a single dose) remaining in the body after different time (half-life) periods.

A drug may also undergo extensive metabolism before fully entering the blood circulation. This process is called first-pass metabolism. The drugs that are eliminated by conjugation (estrogen, progesterone, morphine, etc.) undergo significant firstpass metabolism because the gut is rich in conjugating enzymes. Factors such as gender, disease state, enzyme induction and inhibition, genetic polymorphism, and food may cause significant variability in pharmacokinetics of a drug undergoing first-pass metabolism. Drug concentrations obtained from individuals given the same dose may vary even sevenfold (33).

Renal excretion is a major pathway for the elimination of drugs and their metabolites. Therefore, impaired renal function may cause accumulation of drugs and metabolites in serum, thus increasing the risk of adverse drug effect. This may be particularly important for drugs that have active metabolites, such as procainamide and carba-mazepine. Moreover, other pathological conditions such as liver disease, congestive heart failure, and hypothyroidism may also decrease clearance of drugs. Drugs may also be excreted through other routes, such as biliary excretion. The factors that determine elimination of a drug through the biliary track include chemical structure, polarity, and molecular weight as well as active transport sites within the liver cell membranes for that particular drug. A drug excreted in bile may be reabsorbed from the gastrointestinal track or a drug conjugate may be hydrolyzed by the bacteria of the gut, liberating the original drug, which can return into the blood circulation. Enterohepatic circulation may prolong the effects of a drug. Cholestatic disease states, in which flow of normal bile flow is reduced, will reduce bile clearance of a drug and may cause drug toxicity (34). Moreover, drug-drug interaction may involve bile clearance pathway of a drug. For example, quinidine not only reduces renal clearance of digoxin but also causes an average reduction of 42% in bile clearance of digoxin (35).

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