Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
This chapter reports the study results to determine percutaneous absorption and pharmacokinetics of eflornithine following topical treatment with eflornithine hydrochloride 13.9% cream and “eflornithine–armenicum” composition in rats. The model of aerobic wounds was developed. Eflornithine hydrochloride cream (dose of 460 mg/kg) was applied in group I, and “eflornithine–armenicum” composition was applied in group II at a same dose of Eflornithine. The plasma concentration-time profile of racemic eflornithine following frequent sampling was determined by the HPLC method (LLOQ, 1.5 ng/ml). Eflornithine concentrations were measurable at 24 h, with peak concentrations in plasma 5.3 ng/ml after cream and 3.8 ng/ml after composition application (p < 0.001) and the average time to reach the maximum concentration of eflornithine increases from 2 h to 3.3 h. The area under the pharmacokinetic curve was decreased after composition application by 25%. Eflornithine was eliminated from plasma with a mean terminal half-life of 11.6 hours. It can be assumed that the use of “eflornithine–armenicum” composition allows for maintaining the optimal concentration of two anti-inflammatory compounds at the site of application for a long time, which can improve their pharmacological effect compared to separate use of eflornithine cream.
Institute of Fine Organic Chemistry of the National Academy of Science of the Republic of Armenia, Yerevan, Armenia
*Address all correspondence to: dopingareg@gmail.com
1. Introduction
One of the actual problems of modern medicine is the views and approaches to wound healing, depending on the cause of wounds.
They are numerous, especially depending on the effect of bacteria, such as aerobic and anaerobic, viruses, fungi, injuries to the skin due to burns, and various chemical and physical factors, such as low temperature [1].
In recent years, difficulties in wound healing have been observed mainly due to the ineffectiveness of various widely used antimicrobials, especially antibiotics. It is more severe if it develops against some existing somatic diseases, such as diabetes and non-diabetes mellitus, some acquired connective tissue diseases, congenital and acquired immune deficiencies, etc. The search and development for new effective means of symptomatic-pathogenic treatment of wounds are one of the priorities of modern medicine.
In connection with this, it becomes expedient to carry out pharmacokinetic research to find out the ability of the components of the given composition to remain in the wound.
Studies show that the pharmacokinetics of Eflornithine rats are characterized by a slow systemic blood flow after co-administration of Eflornithine paste to rats, providing a pronounced restorative effect on the wound surface than with Eflornithine alone.
Wound healing has always been fraught with difficulties, as the use of a wide range of antibacterial drugs, including antibiotics, has often been ineffective due to the polymorphic nature of the bacteria found in the wound.
The search for new effective antimicrobials for wound healing, including the development of new formulations the ingredients of which may have a multifaceted inhibitory effect on the growth of bacteria in the wound, is still a very promising direction in modern medicine.
In this regard, Armenicum (ointment and paste) exhibits significant cytotoxic effects on a number of resident conditionally pathogenic bacteria [1, 2].
The authors attribute the effects of “Armenicum” quite well to iodine, which has a direct and/or mediated bactericidal effect by stimulating the activity of radicals in the wounds of diseased tissues [1, 3, 4, 5, 6].
The new composition “Eflornithine–Armenicum” has been developed by taking into account the new scientific interpretations that have appeared in the inflammatory processes of wounds during the last 10 years, which are given below:
“Armenicum” shows the spectrum of antibacterial and anti-inflammatory effects in wound processes caused by aerobic bacteria.
Eflornithine is endowed with a spectrum of antimicrobial activity against pathogenic and conditionally pathogenic resident bacteria containing polyamines.
Using the results of modern scientific research for the treatment of wounds, we found it expedient to develop the drug composition “Eflornithine–Armenicum”, which will be characterized by access restriction of polyamines to microorganisms.
The inclusion of Eflornithine in the composition of the Armenicum will inhibit diabetes and non-diabetes mellitus bacterial persistence in the earliest stages of the local inflammatory process, which will probably lead to a faster and earlier wound-healing process.
It should be noted that pharmacological examinations should be mandatory for the approbation of the therapeutic efficacy of the “Eflornithine–Armenicum” composition on the wound model.
Eflornithine human racemic pharmacokinetics are characterized by an oral bioavailability of approximately 50%, mainly renal elimination (>80%) of low extraction, no reported metabolites, negligible plasma protein binding, and a multiphasic plasma concentration-time profile, probably contributing to highly varying estimates of half-life ranging from 2 to 30 h and percutaneous absorption of topical applications of Eflornithine hydrochloride (HCl) cream is very low (<1%). Absorbed Eflornithine is rapidly eliminated from plasma and predominantly excreted in urine without being metabolized. While the percutaneous absorption of Eflornithine increased after twice-daily topical application, relative to the first application, absorption reached a steady state within four days of twice-daily application and remained low. Trough plasma concentrations also remained constant after four days of twice-daily application. Systemic exposure was low, with steady-state peak and trough plasma concentrations during twice-daily treatment of 10 and 5 ng/ml, respectively, and the terminal half-life averaged 8 to 11 hours. The low degree of percutaneous absorption and low systemic exposure to Eflornithine offer a favorable clinical safety profile of Eflornithine HCl 13.9% cream [7, 8, 9].
The results of the pharmacokinetics study of Armenicum paste following its application on wound surface in two doses showed that the pharmacokinetics of the major active ingredient of Armenicum paste was characterized by slow absorption into the blood and remained on the wound surface for a long time providing more pronounced pharmacological effect [6].
It should be noted that pharmacological studies should serve as an obligatory stage in testing the therapeutic efficacy of the “Eflornithine–Armenicum” composition on a wound model. For this purpose, we carried out pharmacokinetic studies of the medicinal composition created by us on the basis of the pharmacological company “Arpimed” (Armenia) in order to determine the duration of its stay on the wound surface and the rate of absorption from the wounds into the bloodstream.
Vaniqa 11.5% cream (11.5%, Vaniqa, Batch: 838225): Each gram of cream containing 115 mg of Eflornithine hydrochloride monohydrate as the active ingredient, 47.2 mg of cetostearyl alcohol, 14.2 mg of stearyl alcohol, 0.8 mg of methyl parahydroxybenzoate, and 0.32 mg of propyl parahydroxybenzoate (Almirall Limited, Harman House, UB8 1QQ, UK).
To get the 100 g “Eflornithine–Armenicum” composition, add 85 g of Armenicum paste and 15 g of Eflornithine hydrochloride monohydrate (Eflornithine hydrochloride is 13.9 g) to the composition of the container. Stir the mixture at room temperature for 10–15 minutes before using.
The standard used for the Eflornithine hydrochloride monohydrate was the RS USP standard (series R06840). For analytic method validation, the L-ornithine hydrochloride was obtained from Sigma (St. Louis, MO, USA; product A-4571, Batch: 19/L), methanol, high-performance liquid chromatography (HPLC) gradient was obtained from grade Carl Toth GmbH + Co (Art. 7342.1), acetic acid HPLC class was obtained from Carl Roth GmbH (Art. 3738.3), high purity (+99%) acetone was obtained from Carl Roth GmbH (Art. No. 7328.2), and high purity (+99%) dansyl chloride was obtained from Sigma-Aldrich (product –d2625).
1-Heptansulfonic acid sodium salt monohydrate was obtained from Carlo Erba (France Batch No: V8A553138I), distilled water for HPLC (Part No. 5062–8578), Hewlett-Packard, and 0.45-μm nylon filter was obtained from Carl Roth Germany (Carl Roth Germany, Art.7330.1). All chemicals were of analytical grade, and all solvents were of HPLC grade.
2.2 Study animals
A total of 72 non-breed white male rats, bred by the Institute of Fine Organic Chemistry of the National Academy of Science, Yerevan, Armenia, were used in the study. All animals were clinically examined upon arrival and those that showed signs of abnormality or disease were excluded. Animals were kept in the animal house for 10–15 days prior to the commencement of the study under a 12 h/12 h light/dark cycle at 25 to 27°C and 60 to 65% humidity and were offered humidity and were offered standard rat chow ad libitum. Unfit animals were replaced prior to the start of the study, and no animals were replaced after the study began. The initial weights of the study animals were in the range of 160–200 g.
Care of rats and all interventions were performed according to the PHS Guide for the laboratory animals [10] in accordance with requirements of the YSMU Ethics Committee. All experiments were performed during the light phase of the cycle.
2.3 Experimental design
A 4 cm2 wound was incised on the inner surface of the hind leg of animals by the model of aerobic wounds created according to Oganesyan S.S. methodology [11]. After this trauma, the musculoskeletal tissues were compressed twice by the Kocher clamp. The preparations were investigated 5–7 minutes after the onset of the injury: Eflornithine paste or “Eflornithine–Armenicum” composition was applied to the entire wound surface of the animals, which covered all the upper wounds.
Development of aerobic wounds in animals and further operations were performed under ether anesthesia. The animals were kept in isolation without bandages after the wound was healed.
The animals were divided into 2 groups given below:
Group I: 36 rats (mean weight 162 ± 39 g) were treated using a single dose of Eflornithine paste at a dose of 460 mg/kg.
Group II: 36 rats (mean weight 167 ± 37 g) were treated using a single dose of “Eflornithine–Armenicum” composition (Eflornithine: 460 mg/kg, Armenicum: 5.1 mg/kg).
At 0, 2.0, 4.0, 8.0, 12.0, and 24.0 h after the application of investigated preparations, six animals from the both group were sacrificed and blood samples taken.
Following decapitation with a laboratory guillotine, blood was collected from each animal in separate heparinized centrifuge tubes that were centrifuged at 600 g for 15 min in order to obtain blood plasma. An aliquot of plasma (1.0 ml) was taken for Eflornithine assay and the remainder of the sample was conserved by closing the centrifuge tube with a cap and storing it in a freezer for 1–3 days prior to further assay. On the day of the assay, plasma was removed from the refrigerator and stored at room temperature for 1 hour.
2.4 Racemic quantification of Eflornithine
Racemic Eflornithine was quantified using precolumn derivatization, followed by high-performance liquid chromatography (HPLC) and ultraviolet (UV) detection according to published methods [8, 9], modified as described below. The HPLC system consisted Shimadzu LC/UV/MS instrument (LC-20 AD/T, Shimadzu Corporation, Kyoto, Japan) consisting of an autosampler (LC-20 AD/SIL-20A), a UV-diode array detector (SPD-M20A IVDD), and data acquisition and analysis software (Lab Solutions, Version 3.40.299. Shimadzu) set at 330 nm.
Plasma samples (0.5 ml) were precipitated with ice-cold methanol (3 ml) containing an internal standard (DL-4-amino-3-hydroxybutyric acid) at a concentration of 20 ng/ml. The samples were placed on a vortex mixer for approximately 10 s, centrifuged for 10 min at 12,000 g, and thereafter kept at 37°C for 10 minutes. The supernatants were transferred to new tubes and evaporated to dryness at 65°C under a gentle stream of air. The dried samples were dissolved in 100 μl phosphate buffer (0.1 M; pH 7.5). The derivatization mixture was prepared daily by mixing o-phthalaldehyde (20 mg), ethanol (1 ml), nitriloacetic acid (4 mg), mercaptoethanol (100 μl), and 10 ml phosphate buffer (0.1 M; pH 7.5).
Prior to injection, the samples were mixed by adding two 50-μl volumes of derivatization mixture (i.e., o-phthalaldehyde) to the 48-well-plate autoinjector.
The temperature for the autoinjector was kept constant at 20°C. The plasma samples containing the derivatization mixture were programmed to stand in the autoinjector for 2.00 min prior to injection. Eflornithine was separated on a Chromolith Performance RP-18e 100-mm by 4.6-mm-ID column (VWR International, Darmstadt, Germany) protected by a ChromSep Guard SS 10-mm by 2-mm-ID column (Varian, Palo Alto, CA), using a gradient program. Mobile phase A consisted of 92% phosphate buffer (0.1 M; pH 7.5), 5% methanol, and 3% acetonitrile. Mobile phase B consisted of 80% methanol, 10% acetonitrile, and 10% water. The flow rate was set to 2 ml/min, using the following gradient program: t = 0 to 6.75 min, linear decrease of A from 80–40%; t = 6.75 to 8.0 min, 40% A; and t = 8.0 to 10.0 min, linear increase of A from 40–80%. The typical retention times for the internal standard and Eflornithine were 5.5 ± 0.3 min and 7.3 ± 0.2 min, respectively.
Calibration curves, constructed using Eflornithine standards, were linear in the range 1.00–10.0 ng/ml with correlation coefficients (r) of 0.9991, for the target signals at 330 nm. The limit of detection (at a signal/noise ratio of 3) was 0.80 ng/ml and the lower limit of quantification (LLOQ) was 1.5 ng/ml. The LLOQ for racemic Eflornithine was set to 1.5 ng/ml at which level precision and accuracy were < 12%. The experimental plasma samples for method validation were prepared at three concentrations (1.5, 3, and 6 ng/ml) and were analyzed in duplicate at each level during the analytical runs to ensure that experimental samples were accurately and precisely determined. Validation experiments demonstrated that the accuracy was 96.9 ± 3.5%, the precision (coefficient of variation) 3.6%, and the recovery 93.94 ± 2.9%.
2.5 Pharmacokinetic analysis
The pharmacokinetic parameters were calculated using Kinetica 4.4.1 software (Thermo Electron Corporation, 2004, USA).
The measured parameters were as follows:
maximum plasma concentration (Cmax, ng/ml);
elimination rate constant (kel, h−1);
elimination half-life (t1/2, h);
area under concentration versus time curve extrapolated to infinity (AUC0-∞, hng/ml); absorption rate constant (ka, h−1);
the time to Cmax (tmax, h).
2.6 Statistical analysis
Statistical analyses were performed using GraphPad PRISM software (version 2.0, 1996; GraphPad Software, San Diego, USA). The statistical significance of differences between the pharmacokinetics profiles of Eflornithine released from Eflornithine cream and “Eflornithine–Armenicum” composition over time were assessed using two-way between/within ANOVA wherein an interaction effect indicates a different response over time between the two dosage forms.
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.
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).
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 lower (3.33 ± 0.74 h), but the difference between the mean values was not statistically significant (Table 1).
Pharmacokinetics Parameters
Eflornithine HCI cream
“Eflornithine–Armenicum” composition
р
Cmax(ng/ml)
5.362 ± 0.53
3.822 ± 0.42
0.005***
tmax, (h)
2.00 ± 0.00
3.333 ± 0.74
0.363ns
Ka(h−1)
4.595 ± 0.53
3.244 ± 0.54
0.0011**
AUC0-∞ (hng/ml)
76.872 ± 4.72
57.913 ± 3.57
0.0001***
t ½(h)
11.588 ± 0.96
11.761 ± 0.95
0.8131ns
Table 1.
Pharmacokinetic parameter estimates for eflornithine in the rat after application of eflornithine HCI cream and “Eflornithine–Armenicum” composition.
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).
Mean plasma profiles of Eflornithine following topical application of Eflornithine cream and formulation of Eflornithine HCl and “Eflornithine–Armenicum” composition (n = 6, mean ± SD).
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−1 following Eflornithine cream application against 3.244 ± 0,54 h−1 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.
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, 16, 17, 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, 20, 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 long time, which can improve their pharmacological effect compared to the separate use of Eflornithine cream.
Eflornithine concentrations were measurable at 24 h, with peak concentrations in plasma of 5.3 ng/ml after cream and 3.8 ng/ml after composition application (p < 0.001). After combined use of Eflornithine and Armenicum, the average time to reach the maximum concentration of Eflornithine is observed, which increased from 2 h to 3.3 h. The area under the Eflornithine plasma concentration versus time curve was decreased after composition application by 25%. Eflornithine was eliminated from plasma with a mean terminal half-life of 11.6 hours without statistically significant difference after cream and composition application.
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 long time, which can improve their pharmacological effect compared to the separate use of Eflornithine cream.
1.Zilfyan A, Avagyan S, Ghazaryan A. The Effect of Armenicum Paste on the Course of Wound Process. Germany: Monograf LAB LAMBERT Academic Published; 2016
2.Aleksanyan YT, Kamalyan LA, Melik-Andresyan GG. Experimental Study of the Antiviral Effect of the Preparation “Armenicum”. Yerevan: "Armenicum" - Experimental research, Gitutyun; 2000. pp. 49-69
3.Abrahamyan H, Muradyan R, Ghazaryan A, Hovhannisyan A. The pharmacokinetics of Armenicum paste on the rats. Vesnik, S-P. 2009;14:75-78
4.Ghazaryan A, Topchyan H, Hovhannisyan A, Abrahamyan H, Muradyan R. The pharmacokinetics of Armenicum paste tested on the rats. The new Armenian Medical Journal. 2010;4:48-49
5.Abrahamyan H, Hovhannisyan A. Comparative pharmacokinetics of iodide anion after administration of iodine preparations. The new Armenian Medical Journal. 2011;5:26-32
6.Ghazaryan A, Avagyan S, Topchyan H, Zilfyan A. Shifts in the content of samatostatin in blood serum of intact rats under experimentally induced wound process with the application of armenicum drug and paste. The New Armenian Medical Journal. 2016;10:53-56
7.Malhotra B, Noveck R, Behr D, Palmisano M. Percutaneous absorption and pharmacokinetics of Efornithine HCl 13.9% cream in women with unwanted facial hair. Journal of Clinical Pharmacology. 2001;41:972-978
8.Jansson R, Malm M, Roth C, Ashton M. Enantioselective and nonlinear intestinal absorption of Eflornithine in the rat. Antimicrobial Agents and Chemotherapy. 2008;52:2842-2848. DOI: 10.1128/AAC.00050-08
9.Johansson CC, Gennemark P, Artursson P, Äbelö A, Ashton M, Jansson-Löfmark R. Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat. Journal of Pharmacokinetics and Pharmacodynamics. 2013;40:117-128. DOI: 10.1007/s10928.9293-x.012
10.Guide for the Care and Use of Laboratory Animals. Garber JC, editor. Eighth ed. Washington: The National Academic Press; 2011. p. 246
11.Oganesyan SS, Tarverdyan NA, Zilfyan AV. Method of Simulating Abscess, Inventor's certificate number SU 1347089 A1, international number G09B 23/28, 1987 Date of registration: 28.02.1986; Date of publication: 23.10.1987 1987
12.Ritschel WA. Absorption of drugs. Pharmaceutical International. 1974;1:343-346
13.Ritschel WA, Kearns GL. Handbook of Basic Pharmacokinetics Including Clinical Application. 5th ed. Washington, D.C.: American Pharmaceutical Association; 1998. p. 563
14.Gibaldi М. Limitation of classical theories of drug absorption. In: Nimmo LE, editor. Prescott, W.S. Book Drug Absorption. Lancaster: МТР Press Limited Falcon House; 1981. p. 458
15.Griffin CA, Slavik M, Chien J, Hermann G, Thompson O, Blanc GD, et al. Phase I trial and pharmacokinetic study of intravenous and oral alpha-difluoromethylornithine. Investigational New Drugs. 1987;5:177-186
16.Rillema JA, Hill MA. Prolactin regulation of the pendrin-iodide transporter in the mammary gland. American Journal of Physiology. Endocrinology and Metabolism. 2003;284:E25-E28
17.Burri C, Brun R. Eflornithine for the treatment of human African trypanosomiasis. Parasitology Research. 2003;90:S49-S52
18.Na-Bangchang K, Doua F, Konsil J, Hanpitakpong W, Kamanikom B, Kuzoe F. The pharmacokinetics of eflornithine (alphadifluoromethylornithine) in patients with late-stage T.b. gambiense sleeping sickness. European Journal of Clinical Pharmacology. 2004;60:269-278. DOI: 10.1007/s00228-004-0759-7
19.Hayton WL. Rate-limiting barriers to intestinal drug absorption: а review. Journal of Pharmacokinetics and Biopharmaceutics. 1980;8:321
20.Lacroix L, Pourcher T, Magnon C, Bellon N, Talbot M, Intaraphairot T, et al. Expression of the apical iodide transporter in human thyroid tissues: A comparison study with other iodide transporters. The Journal of Clinical Endocrinology and Metabolism. 2004;89:1423-1428
21.Volkenstein MV. Biophysics: Textbook. Allowance. 3rd ed. St. Petersburg; Moscow-Krasnodar: Nauka; 2008. p. 594
Written By
Hovhannes Ghazaryan and Areg Hovhannisyan
Submitted: 06 June 2022Reviewed: 07 June 2022Published: 05 July 2022
Open access peer-reviewed chapter
