1. To see how the liver breaks down efavirenz by an enzyme called CYP2B6. It is suggested that when Efavirenz is taken repeatedly it may increase the amount of CYP2B6 in your liver and thus speed up your liver's ability to get rid of efavirenz from your body. This may render efavirenz and other medications ineffective.
2. To see how efavirenz interact with other drugs taken at the same time with it.
3. To see if genetic differences can change the way how the liver breaks down efavirenz and its interactions with other co-administered drugs.

The human hepatic cytochrome P450 2B6 (CYP2B6) is a key enzyme in the metabolism of a growing list of clinically important drugs, environmental chemicals (e.g. toxicants and carcinogens) and endogenous substances. The expression and activity of this enzyme varies widely among individuals, probably due to genetic polymorphisms in the CYP2B6 gene and drug interactions. This variability, in turn, likely contributes to variable response to those drugs primarily metabolized by CYP2B6. In deed, several drugs that are substrates of CYP2B6 exhibit large pharmacokinetic differences among individuals and their use is associated with unpredictable drug interactions. Therefore, identifying mechanisms and factors that might influence CYP2B6 activity is important to the safe and effective use of its substrates. An important characteristic of several clinically important CYP2B6 substrate drugs that include efavirenz, nevirapine, cyclophosphamide, artemisinin and ifosfamide is their ability to enhance their own clearance upon repeated dosing, a process known as autoinduction of metabolism. Drugs that autoinduce metabolism also exhibit multiple interactions with drug metabolizing enzymes other than CYP2B6 (e.g. CYP3A, CYP2C9 and CYP2C19), and drug transporters (e.g. p-glycoprotein). As most of these medications are used in combination with other drugs, their potential to alter the pharmacokinetics of co-administered drugs is very high. We hypothesize that CYP2B6 genetic variants that influence constitutive CYP2B6 expression and activity contribute to interindividual variability in steady-state exposure of the autoinducer drugs and in the drug interactions that ensue. We will determine the impact of CYP2B6 genetic variants, typically the CYP2B6*6 allele, on the time-course and extent of autoinduction of metabolism and the consequences of differential autoinduction on drug interactions, using efavirenz (a known CYP2B6 substrate and an autoinducer) as a model drug. Thus, single (600 mg oral dose) and steady-state (600 mg/day) pharmacokinetics of efavirenz will be assessed in healthy subjects genotyped for the CYP2B6*6 allele. Trough concentrations of efavirenz and its metabolites will be collected during the course of efavirenz treatment. Efavirenz exposure will be compared between the genotypes after autoinduction. An autoinduction pharmacokinetic model will be developed to characterize the dynamics and time courses of autoinduction in the different genotypes. The potential impact of differences in efavirenz exposure on drug interactions will be determined by measuring the in vivo activity of selected CYP enzymes, using isoform specific substrate probes [omeprazole (CYP2C19), tolbutamide (CYP2C9), caffeine (CYP1A2) and midazolam (CYP3A)] at single and after multiple (steady-state) dosing with efavirenz.

Inclusion Criteria:

1. Male and female subjects between 18 and 49 years old.
2. HIV negative. All potential subjects will be HIV tested at screening visit.
3. Healthy individuals without any significant medical condition.
4. Adherence to the study dietary restrictions.
5. Nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at lest one month prior to and until the completion of the study. The entire study lasts for 30 days.
6. Ability to commit the time requested for this study.

Exclusion Criteria:

1. History or current HIV infection.
2. Life style that places you at a higher risk for contracting HIV (e.g. drug abuse, excessive alcohol drinking, and having multiple sexual partners).
3. Does not consent to HIV testing.
4. Underweight (weigh less than 52 kg or 114 lb) or overweight (body mass index (BMI) greater than 32).
5. History or current alcohol or drug abuse (more than 3 alcoholic drinks per day on a regular basis).
6. History of intolerance or allergic reaction (e.g. rash) to efavirenz, midazolam, tolbutamide, caffeine, or omeprazole.
7. History or current significant health conditions such as heart, liver, or kidney.
8. History or current psychiatric illness such as depression, anxiety, or nervousness.
9. History or current gastrointestinal disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.
10. Individuals having a serious infection within the last month.
11. Donation of blood within the past two months.
12. Blood hemoglobin less than 12.5 mg/dl.
13. Individuals who are regularly taking prescriptions, over-the-counter, herbal or dietary supplements, alternative medications, or hormonal agents (i.e. oral contraceptives, intera-uterine device with hormones).
14. Females with a positive pregnancy test.
15. Breastfeeding.
16. Females of child-bearing potential who are unable or unwilling to either practice abstinence or use two non-hormonal forms of birth control (e.g. condom, contraceptive foams) up until the study completion, which will take a total of 30 days.
17. Participation in a research study or use of an investigational drug in the last two months.
18. An employee or student under supervision of any of the investigators of this study.
19. Individuals who cannot state a good understanding of this study including risks and requirements; are unable to follow the rules of this study.
20. Individuals with a gene type (DNA) that does not match one of the available genetic slot categories.

Adverse events were collected during the study period which was approximately 30 days. I some case, follow-up assessment was carried out up to 2 months after completion of the study and subject was discharged from the study.