Effect of indinavir on the intestinal exsorption of amprenavir, saquinavir and nelfinavir after intravenous administration in rats.
To elucidate drug interaction between human immunodeficiency virus (HIV) protease inhibitors (PIs), the effect of indinavir (IDV) on the intestinal exsorption of other HIV PIs, amprenavir (APV), saquinavir (SQV) and nelfinavir (NFV) was investigated in rats using an in situ single perfusion method. IDV in the intestinal perfusate inhibited the exsorption of rhodamine 123 (Rho123), a known P-glycoprotein (P-gp) substrate, from blood into intestinal lumen in a concentration-dependent manner, and the inhibitory potency of 10 micro M IDV in the perfusate was close to that of 10 micro M cyclosporin A (CsA) in the perfusate. Ten micro M of IDV in the intestinal perfusate also decreased significantly the exsorption clearance of Rho123 after intravenous administration. The IDV concentration in this system was not likely to cause hepatic interaction between HIV PIs, because the plasma IDV concentration was far below its inhibition constants for other HIV PIs in the liver microsomes. Thus, 10 micro M of IDV was chosen to investigate the effect of this inhibition on the exsorption of APV, SQV and NFV. IDV in the intestinal perfusate markedly increased the exsorbed amounts of SQV and NFV but not APV after intravenous administrations. Their exsorption clearances, however, showed only a slight increasing tendency or remained unchanged. These findings suggest that in addition to P-gp inhibition, other factors such as CYP3A inhibition might be important in the drug interaction of IDV with APV, SQV and NFV after intravenous administration in rat small intestine. The results obtained in this study will provide useful information to discuss the interactions among PIs when a double protease therapy is used for in HIV-infected patients.
Gao
Weihua
W
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
Kageyama
Michiharu
M
Inoue
Yuji
Y
Tadano
Jun
J
Fukumoto
Kyoko
K
Fukushima
Keizou
K
Yamasaki
Daisuke
D
Nishimura
Asako
A
Yoshikawa
Yukako
Y
Shibata
Nobuhito
N
Takada
Kanji
K
D000818:Animals; D002219:Carbamates; D004347:Drug Interactions; D005663:Furans; D019469:Indinavir / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D019888:Nelfinavir / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D019258:Saquinavir / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
D002219:Carbamates; D005663:Furans; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir