Cyp2e1 Cyp3a4

Caffeine,b dapsone,b ethanol



Charcoal-broiled beef, cigarette smoke, cruciferous vegetables, marijuana smoke, omeprazole


Phenobarbital, cyclophosphamide (in vitro)

Rifampin, phenytoin, secobarbital


None documented in vivo


Alprazolam, amiodarone, amitriptyline," astemizole, "upropion, caffeine," car"amazepine, cisapride, clarithromycin, clonazepam, codeine," cortisol, cyclosporin, dapsone," desmethyldiazepam," diazepam," diltiazem, erythromycin, estradiol, ethinylestradiol, fluoxetine, haloperidol," imipramine," lidocaine, loratadine, lovastatin, midazolam, nefazodone, nicardipine, nifedipine, omeprazole," ondansetron, orphenadrine, progesterone, quinidine, rifampin, sertraline, tamoxifen, terfenadine, testosterone, trazodone, triazolam, venlafaxine," verapamil," zolpidem

Cimetidine, erythromycin, Barbiturates, fluoxetine, fluvoxamine, carbamazepine, indinavir, ketoconazole, naringenin, nefazodone, ritonavir, saquinavir, sertraline (weak)

dexamethasone, phenytoin, rifampin, St. John's wort aInhi"itory potency varies greatly (see text).

"More than one CYP enzyme is known to "e involved in the meta"olism of these drugs. Source. Ketter et al. 1995; Nemeroff et al. 1996; Schmider et al. 1996.

Certain foods, such as grapefruit juice, can substantially alter the bioavailability of some drugs. Components in grapefruit juice—which contains a variety of suspect candidates, including naringin, other flavonoids, bergamottin, and other furanocoumarins—inhibit intestinal CYP3A4-mediated first-pass metabolism (Paine et al. 2005). The maximal effect can occur within 30 minutes of ingestion of juice. Grapefruit juice may also inhibit the efflux transport of drugs by P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), which are efflux transporters expressed in the human small intestine. The more completely studied of these drug transporters is the transmembrane pump P-gp (also known as the multidrug resistance protein), which causes the adenosine triphosphate (ATP)-dependent efflux of a diverse range of drugs from cells. The distribution of P-gp includes the epithelial cells lining the luminal surface of enterocytes in the small intestine and kidney, making P-gp a critical determinant of oral drug bioavailability and biliary and renal excretion for many drugs (Benet et al. 1999; Silverman 1999). P-gp is also expressed on the luminal surface of the endothelial cells making up the blood-brain barrier and other critical organs. In the gut, P-gp works in concert with CYP3A4 to limit the intestinal absorption of drugs that are common substrates for both proteins.

Changing the route of administration to avoid presystemic metabolism can have a therapeutic advantage. When given orally, selegiline, an irreversible inhibitor of MAO, is substantially converted to several metabolites through extensive first-pass metabolism. Transdermal dosing with drug contained in a removable patch adhering to the skin results in higher systemic exposure to selegiline and lower exposure to metabolites. This allows greater central nervous system (CNS) exposure to selegiline from a given dose to inhibit MAO relative to the required dose from oral administration (Azzaro et al. 2007). Buccal or sublingual administration can also avoid some presystemic drug elimination (Markowitz et al. 2006).

In summary, an important pharmacokinetic principle is that the choice of drug formulation and the route of administration can determine the rate at which the drug and metabolites appear in the systemic circulation. This rate may be manipulated to retard the magnitude of the peak plasma drug concentration when a high peak concentration is related to the occurrence of adverse effects. For example, slow-release formulations of lithium and paroxetine reduce gastrointestinal side effects (DeVane 2003). Alternatively, rapid absorption may be desirable to achieve immediate pharmacological effects.


Drug distribution to tissues begins almost simultaneously with absorption into the systemic circulation. The rate at which distribution occurs will partially influence the onset of pharmacological response. Access to effect sites depends on membrane permeability, the patient's state of hydration, regional blood flow, and other physiological variables. There is increasing evidence that drug transporters in the blood-brain barrier influence drug passage to and accumulation in the brain. Sadeque et al. (2000) demonstrated that loperamide, a potent opiate used to reduce gut motility and not normally distributed to the CNS, produced typical opiate depressant effects on respiratory drive when coadministered with quinidine, a P-gp inhibitor. Physicochemical properties influencing the rate of drug distribution to effect sites include lipid solubility, ionizability, and affinity for plasma proteins and tissue components. Diazepam is highly lipophilic, and its onset of effect is rapid as a result of its entry into the brain within minutes after oral administration (Greenblatt et al. 1980). The concentration of diazepam at its effect site may fall so precipitously as a result of redistribution that its duration of action after an initial dose is shorter than would be expected based on its elimination half-life.

Frequently, the intensity and duration of the pharmacological effect of a second drug dose, taken immediately after cessation of the effect of the first dose, are greater and longer, respectively, than the intensity and duration of the effect of the first dose. This is known as the second-dose effect in pharmacokinetics (DeVane and Liston 2001). When dosing is repeated before the previous dose has been eliminated from the body, the second and subsequent doses produce a greater effect than the initial dose, but the relative intensity of subsequent doses diminishes. This second-dose effect occurs, regardless of the half-life of the drug, when dosing is repeated in response to the observed effect. Common examples of this phenomenon include the self-administration of caffeine and the administration of certain anesthetics.

The predicted time course of drug concentration in plasma and in tissue following a single intravenous drug injection is shown in Figure 8-3. Drug concentration in plasma rapidly declines in a manner consistent with the extensive distribution of the compound out of the systemic circulation. Drug concentration in tissue rapidly increases during this time. Pharmacological effects may not occur immediately but may be delayed until the tissue concentration at the effect site rises above an MEC. An equilibrium eventually occurs between drug in plasma and in tissue. Concentrations from this time forth decline in parallel during a terminal elimination phase.

FIGURE 8-3. Predicted concentration of a drug in plasma and tissue following a rapid intravenous injection.

MEC = minimal effective concentration.

The observed time course of drug concentration changes in plasma has frequently been considered in the pharmacokinetic literature to confer the characteristics on the body of a two-compartment mathematical model (Gibaldi and Perrier 1975). Many drugs appear to be absorbed into a central compartment composed of the circulation and rapidly equilibrating tissues and then distributed to less accessible tissues, which collectively form a peripheral compartment. This compartmentalization of drug concentration greatly aids mathematical analysis of pharmacokinetic data but is clearly an oversimplification, because drug concentrations determined in animal studies can vary over orders of magnitude among different tissues (DeVane and Simpkins 1985).

Even though the drug concentration can vary widely among tissues, equilibrium eventually occurs between drug concentration in plasma and in tissue (see Figure 8-3). The concentration of drug in brain tissue may be substantially different—higher or lower—from that in plasma, but renal and hepatic elimination of drug from the central compartment reducing the plasma drug concentration should be mirrored by a proportional reduction of drug concentration from the brain or other tissues. For this reason, an MEC determined from plasma data may reflect an MEC at the effect site. The distribution of a drug in the body largely depends on the drug's relative binding affinity to plasma proteins and tissue components and the capacity of tissues for drug binding. This pharmacokinetic principle is illustrated in Figure 8-4. Only unbound drug is capable of distributing between plasma and tissues. Different degrees of plasma protein binding among antidepressants, for example, cannot be used to draw valid conclusions about the availability of drug to exert pharmacological effects at the site of action (DeVane 1994). The nonspecific binding of drugs to tissue components complicates the interpretation of the significance of plasma protein-binding differences among drugs. Drug binding in tissues cannot be measured directly in vivo and must be inferred using mathematical models and/or in vitro methods.

FIGURE 8-4. Effect of protein binding on distribution of drug between plasma and tissue.

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