Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in rats

• Published in: Biopharmaceutics & drug disposition Vol. 24; no. 8; pp. 335 - 344
• Main Authors: Shibata, Nobuhito, Kageyama, Michiharu, Kishida, Tomoyuki, Kimura, Keisuke, Yoshikawa, Yukako, Kuwahara, Takeshi, Toh, Jyunichiro, Shirasaka, Takuma, Takada, Kanji
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2003; Wiley
• Subjects: Administration, Oral; Administration, Rectal; Alcohol Drinking - blood; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral Therapy, Highly Active; Antiviral agents; Biological and medical sciences; Drug Monitoring; Ethanol - administration & dosage; ethanol intake; HIV Infections - blood; HIV Infections - drug therapy; HIV protease inhibitor; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - therapeutic use; Humans; Injections, Intravenous; Male; Medical sciences; Metabolic Clearance Rate - drug effects; pharmacokinetic interaction; Pharmacology. Drug treatments; Rats; Rats, Wistar; ritonavir; Ritonavir - blood; Ritonavir - pharmacokinetics; Ritonavir - therapeutic use; saquinavir; Saquinavir - blood; Saquinavir - pharmacokinetics; Saquinavir - therapeutic use; Drug alcohol interaction; Rat; HIV protease inhibitor; Blood plasma; Saquinavir; ritonavir; Antiviral; Consumption; pharmacokinetic interaction; Ethanol; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Retroviridae; Lentivirus; ethanol intake; Virus; Peptidases; Vertebrata; Chemotherapy; Mammalia; Animal; Hydrolases; Human immunodeficiency virus; Pharmacokinetics; Protease inhibitor
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.369

Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV‐infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.78±0.10 to 0.38±0.03 μg h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4‐fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.30±0.06 to 0.57±0.05 μg h/ml and from 17.63±1.66 to 4.18±0.94 μg h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono‐therapy with SQV. This study showed that ethanol‐intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV‐infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake. Copyright © 2003 John Wiley & Sons, Ltd.