Influence of the MDR1 Genotype on Blood Levels of Indinavir and Saquinavir in Healthy Volunteers

INCLUSION CRITERIA: Males and females between the ages of 18 and 60 years. Healthy by medical history and physical exam Laboratory values within established guidelines for participation in clinical studies: AST less than or equal to 2 times ULN (upper limit of normal); Serum creatinine less than or equal to ULN; hemoglobin greater than or equal to 11 g/dL. Ability to abstain from ingesting grapefruit or grapefruit juice 72 hours prior to, and the days of midazolam phenotyping and indinavir and saquinavir administration. Negative serum pregnancy test for females of child-bearing potential. Females of child-bearing potential are able and willing to practice abstinence or use other effective methods of birth control during Phase II of study that do not include oral contraceptives. EXCLUSION CRITERIA: Concomitant routine therapy with any prescription, over the counter, herbal, or holistic medications, including oral contraceptives for 30 days prior to study participation. Subjects must be off oral contraceptives for at least 30 days prior to blood collection for P-gp expression analysis; they must also be off oral contraceptives for at least 30 days prior to midazolam phenotyping, and indinavir and saquinavir administration. Intermittent (PRN) use of acetaminophen and non-steroidal anti-inflammatory medications (i.e. ibuprofen) will be allowed during the study; these medications should not be taken prior to, or within 4 hours of midazolam administration on Day 0. These medications should not be taken during indinavir and saquinavir administration until all blood samples for pharmacokinetic analyses of the respective drugs have been obtained. Subjects will be allowed to take a multivitamin with minerals, or equivalent, once daily if they desire to do so. Inability to obtain venous access for sample collection. Presence of Diabetes mellitus, Human immunodeficiency virus (HIV) infection, cardiac disease (hypertension; congestive heart failure etc.), renal disease (chronic or acute renal failure or insufficiency), respiratory disease (asthma requiring chronic treatment; chronic obstructive pulmonary disease) or any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the investigator. Positive pregnancy test or breastfeeding female. The presence of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs. Drug or alcohol use that may impair safety or adherence. History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty breathing) to indinavir, saquinavir or midazolam. Inability or unwillingness of females of child-bearing potential, to use a non-hormonal (barrier) method of contraception throughout the study (e.g. condom diaphragm etc.). Current cigarette smoker or regular smoker within the past 6 weeks.