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Kong, Jung, Koo, Song, Kim, Han, Lee, and Shin: Pharmacokinetic and Toxicokinetic Studies of Potential Antifungal Compounds, KAF-200522 and KAF-200522·HCl, in Animal Models
Original Article

Lab. Anim. Res. 2010;26(4):399-405.

Published online: 20 January 2010

DOI: https://doi.org/10.5625/lar.2010.26.4.399

Pharmacokinetic and Toxicokinetic Studies of Potential Antifungal Compounds, KAF-200522 and KAF-200522·HCl, in Animal Models

Kwang-Han Kong1, 2, Ju Young Jung1, 2, Kyo Hwan Koo2, Si-Whan Song2, Kap-Ho Kim2, Zhong Ze Han2, Seon-Hwa Lee2, Ho-Chul Shin1, ∗

1College of Veterinary Medicine, Konkuk University, Seoul, Korea

2Preclinical Research Center, Chemon Inc., Yongin, Korea

∗Corresponding author: Ho-Chul Shin, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Korea Tel.: +82-2-450-4056 Fax: +82-2-450-3037 E-mail: hshin@konkuk.ac.kr

Received 11 November 2010       Revised 30 November 2010       Accepted 3 December 2010

Copyright © 2010 Korean Association for Laboratory Animal Science

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Recent researches on clinically used triazole antifungal reagents are focused on their pharmacokinetic disadvantage which increases the probability of inducing adverse effects in patients. For this point, in the present laboratory, Chemon Inc., has investigated new antifungal reactive compounds, KAF-200522 and its chloride form, KAF-200522 · HCl, which has a modified triazole structure. Pharmacokinetic data were measured with LC-MS/MS in male mice which were orally treated with the above compounds at 10 mg/ kg. Tmax and t1/2 of KAF-200522 · HCl were comparable to KAF-200522, but AUC and Cmax were 1.4 and 1.6 times higher than those of KAF-200522, respectively. In beagle dogs, AUC and Cmax of KAF-200522 · HCl were 2.7 and 1.4 times higher than those of KAF-200522, and t1/2 was 3.5 times higher than that of KAF-200522. Moreover, in beagle dogs, the oral bioavailability value of KAF-200522 · HCl was revealed as 31.0% to contrast to 6.2% of KAF-200522. In 1-week repeated oral treatment toxicity study of KAF-200522 in male rats, inhibition of body weight gain was observed in 120 mg/kg treatment group, and loss of body weight was observed in 600 mg/kg treatment group. In the toxicokinetic study of KAF-200522, no accumulation after the systemic exposure was observed. In conclusion, as to the new antifungal drug development, KAF-200522 · HCl was considered to be advantageous in pharmacokinetic characteristics compared to KAF-200522.

Keywords: KAF-200522, KAF-200522 ·, HCl, pharmacokinetic, toxicokinetic, toxicity

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Table 1.
Physical characteristics of KAF-200522 and the synthesis of KAF-200522·HCl
lar-26-399f1.tif
Table 2.
Pharmacokinetic parameters of KAF-200522 and KAF-200522·HCl after a single oral administration of KAF-200522 and KAF-200522·HCl at 10 mg/kg to male mice (n=5, respectively)
Compounds t1/2 (hr) Tmax (hr) Cmax a) (ng/mL) AUC (hr∗ng/mL)
KAF-200522 1.9 1.0 908±151 3687
KAF-200522·HCl 1.7 0.5 1488±2560 5150

a )The standard deviation was calculated only in Cmax because blood collected mice were sacrificed every time point of blood collection due to the sampling method (Blood was taken from the posterior vena).

Table 3.
Pharmacokinetic parameters for KAF-200522 from female beagle dogs after single administrations of KAF-200522 and KAF-200522·HCl at 10 mg/kg (KAF-200522; n=2, KAF-200522·HCl; n=4, respectively)
Compounds Route t1/2 (hr) Tmax (hr) Cmax (ng/mL) AUC (hr∗ng/mL) Fa) (%)
KAF-200522 I.V. 12.8±7.80 –b) 6691±5870 38437±52660  
P.O. 6.0±1.8 1.5±0.7 511±139 2402±5940 6.2
KAF-200522•HCl I.V. 43.9±38.7 – 4987±1237 20909±38410  
P.O. 21.1±6.60 1.4±0.6 746±447 6538±5078 31

a )F means the bioavailability calculated by following formula. F=[AUC(p.o.)/Dose(p.o.)]∗[AUC(i.v.)/Dose(i.v.)]∗100

b )Not applied due to intravenous administration route.

Table 4.
Body weight changes after 1 week repeated oral administrations of KAF-200522 in male rats (n=5)
Dose (mg/kg/day) Weights (g)
Day 0 Day 1 Day 3 Day 6 Gainsa)
  TKb) 182.89±3.71 197.29±5.18 202.53±6.35 226.23±8.67 43.35±5.10
0 Non-TKc) 175.38±6.42 188.13±6.75 195.74±8.33 220.08±7.97 044.7±1.55
  Total 179.88±5.84 193.63±7.07 199.82±7.17 223.77±8.05 43.89±3.76
  TK 180.87±8.13 0182.19±13.83 0188.56±13.34 0214.68±14.94 33.81±6.84
24 Non-TK 184.19±0.07 197.74±1.85 204.14±3.76 225.68±2.04 41.49±1.97
  Total 182.20±6.03 0188.41±13.00 0194.79±12.86 0219.08±12.20 36.88±6.48
  TK 182.83±5.56 181.82±6.71 187.88±9.31 0209.17±11.94 26.34±6.38
120 Non-TK 177.94±6.02 184.66±9.02 0192.67±10.78 0212.56±10.29 34.62±4.27
  Total 180.87±5.63 182.96±6.73 189.79±8.90 0.210.52±10.06∗ ∗∗29.65±6.75∗∗
  TK 180.47±7.66 0157.28±12.73 0165.92±13.94 176.97±6.80 0–3.5±6.91
600 Non-TK 180.18±0.54 160.51±2.94 172.61±1.99 180.73±0.18 –0.55±0.72
  Total 180.35±5.42 0.158.57±9.29∗∗ ∗∗0168.60±10.56∗∗ ∗∗178.47±5.23∗∗ .0–1.88±5.38∗∗

a) Gains are body weight difference between day 0 and day 6.

b) TK represents the data of animals for the toxicokinetic analysis (n=3).

c) Non-TK represents the data of normal animals for the toxicity study (n=2).

∗ Represents a significant difference at p<0.05 or p<0.01 level compared with the vehicle control.

∗∗ Represents a significant difference at p<0.05 or p<0.01 level compared with the vehicle control.

Table 5.
Mean toxicokinetic parameters for KAF-200522 from male Sprague-Dawley rats following 1-week repeated oral administrations of KAF-200522 (n=5)
Dose (mg/kg/day) Period AUC Cmax Tmax
(hr∗ng/mL) (ng/mL) (hr)
24 Day 1 13500±34810 1150±256 2.0±00
Day 7 16521±11127 1394±708 4.0±00
120 Day 1 118185±226130 7792±986 10.0±4.60
Day 7 88340±10947 06587±1194 4.0±1.2
600 Day 1 346502±804860 17768±5874 10.0±000
Day 7 156224±896470 08744±5106 10.0±4.60
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