Non-Linear Pharmacokinetics

Non-linear pharmacokinetic models, as opposed to linear pharmacokinetic models differ in some very critical areas. When the concentration that results from the dose is proportional to that dose and the rate of elimination of the drug is proportional to theconcentration, the drug is said to exhibit linear pharmacokinetics as shown below.

Figure 13-1-1051015202530051015Dose (mg)

C p ( n g / m L )

Figure 13-1-2

02550751000 5 10 15 20 25 30

Time (hr)

C p ( n g / m L )

DoseCp DoseVolume

∝ =

(13.1.1)

CpCpTime

∂− ∝∂

(13.1.2)Integrating equation (13.1.2) results in the first order equation:

Cp Cp e

−

(13.1.3)which can be rewritten to

()()

LN Cp LN Cp KT

= −

(13.1.4)A graph of which is linear with time as shown below.

Figure 13-1-3

110100051015202530

Time (hr)

C p ( n g / m L )

When concentration that results from the dose is not proportional to that dose and/or therate of elimination of the drug is not proportional to the concentration, the drug is said toexhibit non-linear kinetics as shown below.

Figure 13-1-4

0102030405060708090100

0 100 200 300 400 500

Dose/day

C p ( n g / m L )

a v e

Figure 13-1-5

010020030040050060070080090010000 10 20 30 40

Time (hours)

C p ( n g / m L )

If we were to plot LN(Cp) vs Time as in figure (13.1.4), we would observe the following:

Figure 13-1-6

11010010000 10 20 30 40

Time (hours)

C p ( n g / m L )

Compare the terminal portion of the curve (time>25 hours) of figures 5 and 6 with figures2 and 3. Looks similar, doesn’t it. Well, there’s a reason for it. In many cases, the rateof elimination of the drug is defined by the enzymatic metabolism. From biochemistry,we (should) remember the Michaelis-Menten equation that describes the rate of substratemetabolism.

( )

max

V C C t K C

∂= −∂ +

(13.1.5)Where V

max

= the maximum velocity capable by the enzymesK

= drug concentration that is metabolized at half themaximum velocity

Drugs that exhibit this kind of behavior are said to exhibit non-linear pharmacokinetics.Let’s look at the various portions of the curve. There are three distinct portions of thiscurve:1)

The initial straight portion of the figure 13-1-5 (Cp >> K

)2)

The middle curved portion of figure 13-1-5 and 13-1-6 (Cp

≈

)3)

The terminal straight portion of figure 13-1-6 (Cp << K

)

If (Cp >> K

)

then equation (13.1.5) becomes:

( )

0maxmax

V C C V KC t C

∂− = − = −∂



(13.1.6)What we see is that the enzymatic activity is maxed out and the rate of elimination of thedrug is constant or, in math speak, the elimination rate is proportional to C to the zero power. (Math review A

=1, Chapter 2.) Thus

KC K

− = −

. Drugs that exhibit this kindof behavior are said to exhibit

zero order behavior

. The concentration is changed at aconstant rate,

X mg/hour

are removed by the metabolizing enzymes.

If (Cp << K

)

then equation (13.1.5) becomes:

( )

1max

V C C KC t K

∂= − = −∂

(13.1.7)where

( )

max

V K K

Drugs that exhibit this kind of behavior are said to exhibit

first order behavior

. Theconcentration is changed at a rate proportional to the concentration,

X%/hour

is removed by the metabolizing enzymes. Note equation (13.1.7) is identical to equation (13.1.2). Thus, what we see for a majorityof drugs is that equations (13.1.3) and (13.1.4) describe their pharmacokinetics becausethe enzymes in the body are very efficient in the drug’s removal and the therapeuticconcentrations are well below the drug’s K

.If (Cp

≈

) then the whole equation must be used and not just the limits as shownabove.Why is this important? Because for those drugs where this is occurring, unlike drugs thatexhibit linear kinetics, where a change in daily dose results in a proportional change in plasma concentration, as in the initial portion of figure 13-1-4 (< 200 mg/day), a smallchange in daily dose could result in a LARGE change in plasma concentration, as shownin the terminal portion of figure 13-1-4 (> 400 mg/day). In other words something like a10% change in dose would not yield a 10% change in concentration but could yield a100% (or greater) change in concentration. This could lead to toxicity.