| TABLE 3 |
| LOCATION AND FUNCTION OF P-GP |
| ORGAN/TISSUE | SITE | FUNCTION |
|
Gut
Colon
Jejunum
| Apical (luminal) surfaces of superficial columnar epithelial cells | Intestinal excretion and reduced absorption of drugs and toxins |
| Liver and Biliary System | Hepatocytes on biliary canalicular front | Hepatobiliary excretion of drugs and toxins |
| Apical (luminal) surfaces of epithelial cells of small biliary ductules |
| Hepatocytes | Regulation of cytochrome expression |
| Pancreas | Apical surfaces of epithelial cells of small ductules | Unknown |
| Kidney | Apical surfaces of epithelial cells of proximal tubules | Urinary excretion of drugs and toxins |
| Brain | Luminal surfaces of endothelial cells of cerebral capillaries |
Contributes to the blood-brain barrier, keeping drugs and toxins out of the brain |
| Choroid plexus | Unknown |
| Peripheral Nerves | Endothelial cells of nerve capillaries | Contributes to the blood-nerve barrier, keeping drugs and toxins out of nerves |
| Uterus | Fetally-derived epithelial cells of placenta |
Contributes to the materno-fetal barrier, keeping drugs and toxins out of the fetus |
| Steroid-producing cells of endometrial glands | Unknown - possible role in steroid production |
| Testis and Ovary | Capillary endothelial cells | Contributes to the blood-testis/ovary barrier, keeping drugs and toxins out of the gonads |
| Immune System | Skin dendritic cells | Migration of dendritic cells to lymph nodes |
| Activated lymphocytes | Transport of some cytokines (especially interleukins-1, 2, 4 and interferon-y) out of cell |
| Natural killer and CD8+ cytotoxic T cells | Reduced cytolytic activity |
| Bone Marrow | Hematopoietic stem cells | May remove drugs and toxins from the bone marrow |
| Adrenal Gland | Medulla and cortex | Unknown - possible role in steroid production |
| Large arteries | Endothelium | Unknown - possible role in accumulation of intracellular cholesterol ester in atherosclerotic lesions |
| TABLE 4 |
| AREAS FOR FURTHER RESEARCH |
| Further research on P-gp is needed in the following areas: |
1. Related to HIV Disease and Progression
P-gp expression and function in HIV-infection - both in different tissues of the body as well as in various stages of disease
The possibility of using P-gp function and expression as one of the surrogate markers for HIV disease progression
The effects of P-gp expression - and alterations in P-gp expression
– on HIV infectivity
– on the immune systems of HIV-infected individuals
– on HIV therapy
The role of P-gp in viral failure and the development of resistance to PIs |
2. Related to Treatment for HIV
The safety and efficacy of P-gp modulation in the management of HIV disease, especially during the use of PI-containing regimens
– Do the modulators affect P-gp differently in different tissues?
Inhibition of P-gp transport by RTV (and possibly other PIs)
Clinical value of using RTV (and other PIs) as a P-gp inhibitor
– Safety and efficacy
– Optimal therapeutic dose(s) of RTV (and that of other PIs) required
Effects of P-gp on intracellular concentrations of PIs in HIV infected cells and on tissue penetration of PIs
Effects of P-gp on concomitantly administered drugs
|
| 3. Related to the Cytochrome System
Pharmacokinetic interactions and interdependence of the P-gp transport and the cytochrome metabolic systems |
4. Mother-to-Child Transmission
Safety and efficacy of co-administration of P-gp inhibitors with PIs is for prophylaxis of vertical transmission
– The optimal time to administer P-gp inhibitors to minimize the adverse effects of drugs and toxins on the developing fetus would need to be determined |
| 5. Cholesterol Metabolism and Dyslipidemias
The mechanism of action of PI-induced dyslipidemias and what role, if any, P-gp plays
Whether HIV disease itself affects the role of P-gp in cholesterol metabolism
|
Basic Science Index