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Clinical Pharmacology of SSRI's
10 - Appendix

As discussed in Section 8, the in vitro inhibition constant (Ki) is not the sole determinant of whether a drug will produce a clinically meaningful or even detectable in vivo effect on a cytochrome P450 (CYP) enzyme under clinically relevant dosing conditions. Instead, it is only one factor in the equation:

Equation 1:

of Effect
= Affinity for Site of Action x Drug Concentration of Effect at Site of Action x Underlying Biology of Patient

For this reason, the Ki has relatively limited value without knowing or at least having a reasonable estimate of the concentration of the potential inhibitor at the site of action (eg, the CYP enzyme). Parenthetically, the location of the relevant CYP enzyme may be extrahepatic in some instances, such as in the gut wall in the case of the inhibition of the first pass metabolism of terfenadine.

Although some reviews have attempted to rank or list drugs as enzyme inhibitors based on primarily in vitro data or isolated case reports of possible interactions,2 this approach does not convey to the clinician whether an interaction is likely to occur in clinical practice or to what extent. Answers to these questions require knowing the concentration of the drug that will occur under clinically relevant dosing conditions as well as the Ki.

This appendix is for the reader who would like more background on this issue from a mathematical perspective, but is not intended to be a rigorous mathematical treatise on the subject. This discussion is relevant to any drug or class of drugs capable of inhibiting a CYP enzyme; however, it will use the SSRIs as the example since they are the subject of this book. The reader who would like further discussion of these matters is referred to the work of Segel3 and von Moltke and colleagues.4

For this discussion, we must recall some basic principles of biochemistry, specifically enzymology. The relationship between the inhibition of an enzyme caused by a competitive inhibitor and the concentration of the inhibitor is expressed by the equation:

Equation 2:

i = [I] / ( [I] + Ki (1 + [S] / Km) )

where “i” is the fractional inhibition of the enzyme, [I] is the concentration of the inhibitor, Ki is the inhibition constant of the inhibitor for the enzyme, [S] is the concentration of the substrate normally biotransformed by the enzyme, and Km is the affinity constant of that substrate for that enzyme.

If [S] is less than Km as is the case in vivo for drugs with linear pharmacokinetics,then the fractional inhibition is independent of the substrate concentration and the equation reduces to:

Equation 3:

i = [I] / ( [I] + Ki )

Hence, to the first approximation, the fractional inhibition of the enzyme is determined by the concentration of the inhibitor directly and by the Ki of the inhibitor reciprocally. The smaller Ki is to [I], the more “i” approaches unity:

Equation 4:

i = [I] / [I] (when Ki <<<< [I])

Equation 4 illustrates why both Ki and [I] are important when trying to determine whether a clinically meaningful degree of enzyme inhibition is likely to occur under clinically relevant dosing conditions. Parenthetically, the relative Ki’s in some studies (eg, Crewe et al, 1991) can be outliers relative to the ones derived from other in vitro studies (Table 8.7). If the concentration of the substrate used in the study not being much less than its Km and not reflective of what would be expected in vivo.

Since all of the SSRIs except possibly fluvoxamine have “active” metabolites in terms of the inhibition of specific CYP enzymes such as CYP 2D6, one must have equation 3 for the parent drug and all of its relevant metabolites when doing projections from in vitro work to in vivo reality. Parenthetically, formal in vivo pharmacokinetic studies measure the summed effect of the parent drug and all of the relevant metabolites at the relative concentrations that they occur under clinically relevant dosing conditions, assuming that the drug is given as it would normally be given and given for a sufficient period of time to reach steady-state conditions.

This last condition has not been true for many of the fluoxetine studies reviewed in Section 8. Instead, loading dose strategies (eg, 60 mg/day × 8 days) have commonly been used due to the long period of time that the study will have to go to reach steady-state conditions of fluoxetine and norfluoxetine. The results of such loading dose strategies may underestimate the actual effect that will occur under more clinically relevant dosing conditions for several reasons. First, norfluoxetine is more potent than fluoxetine in terms of the inhibition of some CYP enzymes such as CYP 3A3/4. Secondly, the conversion of fluoxetine to norfluoxetine takes time. Third, this conversion is inhibited by high concentrations of fluoxetine and/or norfluoxetine. Hence, such loading dose approaches may underestimate the ratio of norfluoxetine to fluoxetine that will be expected under truly steady-state conditions and thus underestimate the concentration of the more portent CYP 3A3/4 inhibitor, norfluoxetine. For these reasons, the results from the loading studies with fluoxetine must be interpreted cautiously and do not reflect the effect that will occur under steady-state conditions at at 20 mg/day, much less 60 mg/day.

The next step in trying to relate in vitro results to in vivo reality is to determine what is the relevant concentration at the CYP enzyme. The concentration of the drug in plasma is the most readily measured concentration; however, the enzyme is not in the plasma, but rather in some tissue compartments. The hepatic tissue compartment is the one which is generally most relevant to predicting whether a pharmacokinetic drug-drug interaction is likely to occur due to the inhibition of a CYP enzyme. For this reason, we need to either measure or estimate the hepatic concentration of the drug which occurs in this compartment under clinically relevant dosing conditions.

Typically, the hepatic concentration is estimated rather than directly measured. It is estimated based on measuring the plasma drug concentration of the drug and its plasma:liver partition coefficient (Table 10.1). The plasma:liver partition coefficient is empirically determined in animals and then can be confirmed in man using autopsy or surgical material.

Table 10.1 illustrates how such information can be used to estimate the relative inhibition of a specific CYP enzyme using such information. Table 10.1 compares the estimated inhibition of CYP 2D6 by 4 different SSRIs. First, the average Ki for each SSRI was calculated using the data from the 5 in vitro studies reported in Table 8.7. Since all 5 of these studies measured the Ki for fluoxetine but not for all the other SSRIs, the average Ki for fluoxetine was determined and used to normalize the Ki values for all the other SSRIs in terms of their relative value compared to fluoxetine. The plasma levels of the different SSRIs which would be expected under comparable antidepressant treatment conditions was then determined. The hepatic concentration of each SSRI which would be expected under such conditions was then estimated based on each drug’s plasma:liver partition coefficient times their expected plasma drug concentration at steady-state under comparable antidepressant treatment conditions. These values and equation 2 above correctly predict the substantial differences in the degree of CYP2D6 inhibition which has been measured in the 11 formal in vivo pharmacokinetic studies reviewed in Section 8 on the relative effects of these SSRIs on CYP 2D6 function. As can be readily seen, a comparison using the Ki alone will lead one to erroneously conclude that there may be minimal differences between these different SSRIs with regard to the inhibition of this enzyme under clinically relevant conditions.

The next issue is how the fractional inhibition of the enzyme relates to the change in the concentration of a concomitantly administered drug which is dependent on the functional integrity of this enzyme for its clearance. In clinical practice, the term “concentration” usually refers to either a 12-hour post-dose concentration or a trough concentration (ie, the concentration immediately before the next dose of drug is given). In both instances, these concentrations are typically measured after steady-state has been attained or assumed to have been attained. A more rigorous measurement is to measure the area under the plasma concentration-time curve (AUC) under steady-state conditions. The latter approach is typically used in formal pharmacokinetic studies. Nonetheless, both approaches have been used to assess the change in the drug concentration as a function of the decrease in its clearance produced by the inhibition of the principal CYP enzyme responsible for the biotransformation necessary for the drug’s elimination. The increase in the AUC with the inhibitor present (AUCi) relative to the AUC without the inhibitor present is related to the fractional inhibition of the enzyme (i) as follows:

Equation 5:

AUCi/AUCo = I/ ( 1-I )

As can be readily appreciated, equation 5 describes a complex hyperbolic relationship (Figure 10.1) between the fractional inhibition of the enzyme and the change in the plasma concentration of the drug whose metabolism has been inhibited. This curve approximates linearity over narrow portions of the curve. As the inhibitions increase, the increase in the plasma concentration of the affected drug increases disproportionately. This fact further explains the differences in clearance of drugs such as desipramine which are observed when fluoxetine and paroxetine are coprescribed at their usually effective minimum antidepressant doses versus citalopram, fluvoxamine, and sertraline (Table 10.1). Fluoxetine and paroxetine produce substantially more than 50% inhibition of the enzyme in contrast to the other 3 SSRIs and thus are on the rapidly ascending portion of this hyperbolic curve.

As stated at the beginning, this discussion has used the effect of the SSRIs on CYP 2D6 to illustrate the enzymological and pharmacokinetic principles relevant to understanding in greater depth the differential effects of drug-induced inhibition of CYP enzyme-mediated clearance of concomitantly prescribed drugs. These principles are relevant to the effects of the SSRIs on other CYP enzymes and to the effects of other drugs on the various CYP enzymes.

TABLE 10.1 Variables Which Determine the Magnitude of the Effect In Vivo: CYP 2D6 as an Example
  Fluvoxamine Fluoxetine Paroxetine Sertraline
Relative Ki 9.4 1.0 0.8 6.4
Estimated Ki (M) 8.31 0.88 0.71 5.66
Plasma concentration (nM) 164.0 512.0 135.0 66.0
Liver:water partition ratio 26.6 12.1 26.2 12.2
Liver concentration (M) 4.4 6.2 3.5 0.8
Change in desipramine*
    PK studies (AUC)


380% to 640%

327% to 421%

0% to 37%
* Above baseline.
AUC = Area under curve.
References: 120

Using the approach explained above, in vitro studies can be used to screen already marketed drugs or drugs in the development for their effects on CYP enzymes and to predict using a knowledge of their Ki, the plasma drug concentration expected under clinically relevant dosing conditions and the plasma:liver partition coefficient whether a clinically meaningful change in the clearance of specific drugs can be expected if they were concomitantly administered with the potential inhibitor. Based on such in vitro modeling, appropriate in vivo studies can be done on a selective basis to confirm such predictions when such an interaction would be predicted to occur in a significant number of patients (ie, the drugs are likely to be frequently coprescribed together) and the consequences are predicted to be clinically important. The advantage of this sequential in vitro and then in vivo approach is the cost and time efficiency of doing in vitro rather than in vivo studies to screen the drugs against a full battery of CYP enzymes.

Given this discussion, readers can anticipate that they will be hearing more and more about the effects of a wide variety of drugs on CYP enzymes. This information will aid the physicians in anticipating pharmacokinetic interactions and will allow them to make appropriate treatment decisions (eg, drug selection, dose adjustments) to avoid adverse consequences of such interactions. The SSRIs and their differential effects on CYP enzymes have been a significant impetus and vehicle for educating physicians about this important advance in our knowledge.

TABLE 10.2 SSRIs: Brand Names by Country
Country Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline
Argentina -- Animex-On
-- Aropax Zoloft
Australia -- Prozac 20 -- Aropax Zoloft
Austria Seropram Fluctine Floxyfral Seroxat Tresleen
Belgium Cipramil Prozac Floxyfral Aropax
Canada -- Prozac Luvox Paxil Zoloft
Denmark Cipramil Fontex
Fevarin Seroxat Zoloft
Finland Cipramil Fontex
Fevarin Seroxat Zoloft
France Cipramil Prozac Floxyfral Deroxat Zoloft
Germany Saroten Fluctin Fevarin Seroxat
Greece Seropram Flonital
Dumyrox Seroxat --
Italy -- Fluxeren
Mexico -- Fluoxac
-- Aropax
Netherlands -- Prozac Fevarin Seroxat Zoloft
Norway Cipramil Fontex Fevarin Seroxat Zoloft
Portugal -- Digassim
Dumyrox -- --
South Africa Cipramil Prozac Luvox Aropax 20 Zoloft
Spain -- Adofen
Dumirox Frosinor
Sweden Cipramil -- Fevarin Seroxat Zoloft
Switzerland Seropram Fluctine Floxyfral Deroxat Zoloft
Turkey -- Depreks
Faverin -- Lustral
United Kingdom -- Prozac Faverin -- Lustral
United States -- Prozac Luvox Paxil Zoloft
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