| Pharmacokinetics of a new anti-HIV agent VP-0501 and development of its amino acid prodrug for improving oral bioavailability |
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Hee-Jeong Cho, Kyung-Ae Choi, Ji-Min Sung, Sang-Min Jeong, Jin-Soo Han, Jin-Suk Kim, Ho-Chul Shin |
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College of Veterinary Medicine, Konkuk University |
| Anti-HIV agent VP-0501의 생체이용성 향상을 위한 아미노산 프로드럭 개발 및 약물동태연구 |
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조희정, 채경애, 성지민, 정상민, 한진수, 김진석, 신호철 |
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건국대학교 수의과대학 |
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| Abstract |
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We have studied pharmacokinetics of a new anti-human immunodeficiency virus (HIV) agent VP-0501 and its amino acid prodrug VP-0501AL which is designed to improve oral bioavailability. After oral administration at 100 mg/kg dose in rats (n = 4), VP-0501 was not detectable in plasma (<50 ng/ml), while after the administration of VP-0501AL, VP-0501 was quantitatively detected, at least for 8 hrs, with Cmax of ca. $2.5{mu}g/ml$ and AUC of $8hr^{ast}{mu}g/ml$. When VP-0501 was intravenously administered at 50mg/kg, this compound appeared at a marginal level in plasma with AUC of $2hr^{ast}{mu}g/ml$, $t_{1/2}$ of 2 hr, $C_0$ of $0.7{mu}g/ml$, and MRT of 3 hr. On the other hand, with intravenous VP-0501AL at the same dose, both the prodrug VP-0501AL and its metabolite VP-0501 appeared comparatively at higher level in the plasma: pharmacokinetic parameters of VP-0501AL including $Vd_{eta}$, AUC, $t_{1/2,{eta}}$, $C_0$, $CL_{tot}$, and MRT were ca. 2 L/kg, $70hr^{ast}{mu}g/ml$, 2 hr, $180{mu}g/ml$, 0.7 L/hr/kg, and 1 hr, respectively. These results demonstrate that attachment of amino acid alanine to VP-0501 is an effective approach for improvement of its oral bioavailability. Therefore, VP-0501AL is expected to become a new highly bioavailable and potent anti-AIDS drug candidate/lead compound. |
| Key Words:
AIDS, pharmacokinetics, prodrug, VP-4051 |
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