**3. Results**

The pharmacokinetic profiles of Eflornithine determined in control rats (Group I) and in those (Group II) that had been treated with "Eflornithine -Armenicum" composition are shown in **Figure 1**.

Maximum plasma concentrations of Eflornithine (Cmax) averaged 5.193 ± 0.74 ng/ ml after Eflornithine cream application in Group I and decreased following "Eflornithine–Armenicum" composition 3.716 ± 1.198 ng/ml.

A comparison of the two pharmacokinetic profiles of Eflornithine indicates that the concentration of Eflornithine in the blood plasma of animals treated with Eflornithine cream was slightly higher than in that of the "Eflornithine–Armenicum" composition group during the 2–24 h following application and attained its maximum value (Cmax) at 2.00 h.

For Group II treated with "Eflornithine–Armenicum" composition, the observed average time to reach maximum concentration in blood plasma (tmax) was slightly

#### **Figure 1.**

*Mean plasma profiles of Eflornithine following topical application of Eflornithine cream (group I) formulation of HCl and "Eflornithine–Armenicum" composition (group II) (n = 6, mean ± SD).*

*Comparison of the Pharmacokinetics of Eflornithine after Application of Eflornithine Cream… DOI: http://dx.doi.org/10.5772/intechopen.105742*

lower (3.33 ± 0.74 h), but the difference between the mean values was not statistically significant (**Table 1**).

After reaching the maximum, the pharmacokinetic profile of the Eflornithine concentration in plasma is almost the same in both groups (**Table 2** and **Figure 1**).

The values for the average elimination half-life (t1/2) and of Eflornithine were very similar for both groups: (11.600 ± 0.961 h and 11.761 ± 0.956 h for groups I and group II, respectively), and the difference between the mean values was not statistically significant (**Table 1**).

Notable differences were found; however, in the absorption rate constant (ka) of Eflornithine, which was higher in the Eflornithine cream-treated group and averaged 4.595 ± 0,53 h<sup>−</sup><sup>1</sup> following Eflornithine cream application against 3.244 ± 0,54 h<sup>−</sup><sup>1</sup> for "Eflornithine–Armenicum" composition treated group and the difference between the mean values was statistically significant (**Table 1**).

The areas under the concentration-time curve AUC0-∞ were also different between the control group and the group treated with "Eflornithine–Armenicum" composition. The difference between the mean values was statistically significant (**Table 1**).

The results showed that when Eflornithine was used concomitantly with Armenicum and the maximum plasma concentrations of Eflornithine were approximately 30% lower than those of Eflornithine cream. The total amount of Eflornithine in blood plasma (AUC0-∞) also decreased by 23%. This indicates that Eflornithine enters the bloodstream from the application site significantly more slowly and to a lesser extent when used in combination with Armenicum.


#### **Table 1.**

*Pharmacokinetic parameter estimates for eflornithine in the rat after application of eflornithine HCI cream and "Eflornithine–Armenicum" composition.*


#### **Table 2.**

*Mean plasma profiles of Eflornithine following topical application of Eflornithine cream and formulation of Eflornithine HCl and "Eflornithine–Armenicum" composition (n = 6, mean ± SD).*

Thus, it is possible that Eflornithine can remain on the surface of the site of application for a longer time, which probably contributes to the longer manifestation of its local anti-inflammatory effect.

If the theoretical data obtained are correct, then in practice, we can calculate the relative bioavailability of Eflornithine using the method of Ritschel and Kearns (1998), after its co-administration with Armenicum [12, 13].

According to generally accepted pharmacokinetic approaches, if two dosage forms contain the same substance in the same dosage and are used in combination with another substance, it is possible to assess its relative bioavailability by setting the bioavailability of the first dosage form at 100%, if this ingredient has been used alone, and has the same dosage in the investigated pharmaceutical form [12, 13].

The percent of relative bioavailability of Eflornithine was calculated as a ratio of Eflornithine's AUC0-∞ after applying "Eflornithine–Armenicum" and AUC0-∞ of Eflornithine after applying Eflornithine cream.

The results of the calculation showed that the relative bioavailability of Eflornithine after application of "Eflornithine–Armenicum" composition is 77.4 ± 6.04% of the bioavailability obtained following the application of Eflornithine cream alone.

Given the fact that the elimination rate of the drug after reaching the maximum concentration in blood is practically the same, it can be assumed that decreased relative bioavailability of Eflornithine is probably associated primarily with its lower and slower absorption of Eflornithine to the systemic circulation from the application site, following the application of "Eflornithine–Armenicum" composition [14].

As known from the literature data, in particular, the percutaneous absorption of Eflornithine remains low (less than 1% of the dose, based on excretion of radioactivity in urine and feces) after single and multiple doses applied under conditions of clinical use. The obtained data are largely similar to those obtained by Malhotra B. and coauthors [7], who confirmed that the average transdermal absorption of Eflornithine to blood plasma after Eflornithine cream application is approximately 1–2% of the radioactive dose. The authors concluded that the percutaneous absorption may correspond to a zero-order kinetic absorption.

The latter presupposition allows concluding that Eflornithine is probably absorbed into the bloodstream after percutaneous application by nonlinear absorption kinetics, which is in line with the previous conclusion by several authors [15–18].

The data do not exclude the possibility that the transfer of Eflornithine from the application surface to the general bloodstream occurs through active carriers. The kinetics of this process was very different from ordinary passive transport.

A system that performs such special transport of compounds through biomembranes (involving carriers) usually has a limited capacity [14, 19–21].

It can be assumed that when the "Eflornithine–Armenicum" composition was used, two biologically active substances of Armenicum, iodide-dextrin and eflornithine, can compete with each other for space on the carrier since it has previously been shown that the iodide anion can also be transported through biomembranes using carriers [1, 4, 5].

Consequently, as the density of the Eflornithine–iodine–dextrin complex increases at the surface of application, their penetration rate into the bloodstream reaches a constant value at some point from the site of application, leading to a slow absorption process. Thus, it can be assumed that the combined use of Eflornithine and Armenicum in the form of a composition allows for maintaining the optimal concentration of two anti-inflammatory compounds at the site of application for a

*Comparison of the Pharmacokinetics of Eflornithine after Application of Eflornithine Cream… DOI: http://dx.doi.org/10.5772/intechopen.105742*

long time, which can improve their pharmacological effect compared to the separate use of Eflornithine cream.
