How genetic variations affect drug interactions with efavirenz, methadone, and tizanidine

Inclusion Criteria:

Subjects will be included in the study if participants:

* are male and female (approximately 1:1) volunteers between the age of 18 and 65 years old
* are judged healthy without any significant medical condition as determined by and decided from a pre-enrollment screening session that include medical history, laboratory tests such as blood and urine tests, vital signs, and an electrical tracing of the heartbeat (electrocardiogram, EKG). The pre-enrollment screening will be done no more than six weeks before the start of the study.
* are able and willing to adhere to the study medication restrictions two weeks before initiating the study and during the conduct of the entire study. These will include refraining from taking any prescriptions medications, over-the-counter medications, and herbal, dietary, and alternative supplements that may interact with the metabolism of those study drugs at least 2 weeks prior to the start of the study and until study completion.
* are nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at least two weeks prior to and until the completion of the study.
* are willing to commit the time requested for this study.

Exclusion Criteria:

* Subjects will be excluded from the study if participants:

  * are underweight (weigh less than 50 kg or 110 lb.) or overweight \[BMI greater than 32\]. Body mass index is calculated using height and weight to estimate how much body fat subjects have.
  * have laboratory results that do not fall in a healthy range
  * have an electrical tracing (baseline EKG readings) that are abnormal as decided by the study physician (medical doctor).
  * have history of intolerance, allergic reactions (e.g., rash) or other forms of hypersensitivities to any of the study medications (efavirenz, tizanidine or methadone).
  * Have a hemoglobin count below the normal range (male \<13.4 gm/dL: and female \<12 gm/dL)
  * have a positive pregnancy urine test (if female) obtained just prior to each study.
  * are sexually active, who is unable or unwilling to use an appropriate and effective method of birth control (for example barrier methods like diaphragms or condoms) to avoid the possibility of becoming pregnant
  * are night shift workers in which case taking efavirenz may interfere with their work.
  * have any significant health condition such heart, liver, or kidney disease
  * have history or current seizures which may lead to collapse.
  * have history or current mental illness (brain) such as feeling sad or unhappy, loss of interest in normal activities, worried or suicidality (thoughts about or an unusual preoccupation with ending own life) or suicide attempts.
  * have gastrointestinal (digestive) disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.
  * have history or current psychiatric disorders such as depression, anxiety, or suicidality or suicide attempts that may be exacerbated by participation in the study
  * have a history of or current HIV infection or have a lifestyle that places participants at a higher risk for contracting HIV (e.g., drug abuse, excessive alcohol drinking, and having multiple sexual partners).
  * take more than 2 alcoholic drinks per day on a regular basis for two weeks prior to the study and unwilling to stop alcoholic drinks during the study
  * unwilling or unable to stop taking drugs of abuse, including tobacco products or marijuana, two weeks prior to and during the entire study period
  * have a systolic blood pressure lower than 70 mm Hg which may place subjects on high risk for tizanidine induced hypotension
  * have participated in a research study involving intensive blood sampling or have donated blood within the past two months.
  * are taking prescription medications, over-the-counter medications, herbal or dietary supplements, and alternative medicines that may interfere with the metabolism of the study drugs (e.g., inhibitors or inducers of CYP2B6 or CYP1A2) and are unable or unwilling to stop taking these medications two weeks prior to and during the entire study period.
  * are employees or students under supervision of any of the study investigators.
  * cannot state a good understanding of this study including risks and requirements
  * are unable to follow the rules of this study.
  * cannot or unwilling to commit the time requested for this study.