Serum Zidovudine and Zidovudine-Glucuronide
Study Objective. To characterize the concentration-time profiles of zidovudine and zidovudine-glucuronide in semen and serum of men infected with the human immunodeficiency-1 virus (HIV-1).
Design. Open-label observational study.
Setting. University-affiliated teaching hospital and research center.
Patients. Four asymptomatic HIV-1-infected men.
Interventions. Zidovudine administration was followed by an 8-hour intensive pharmacokinetic study on day 1. Over the next 8 days, a dose administration and timed single-sample strategy was employed to determine serum and semen concentration time profiles simultaneously.
Measurements and Main Results. Zidovudine and zidovudine-glucuronide concentrations were uniformly higher in semen than in serum except at 1 hour after the dose. The median area under the curve ratio (semen AUC0-48:serum AUC0-[infinity]) was 3.31 for zidovudine and 15.04 for zidovudine-glucuronide.
Conclusion. Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.
With the advent of combination antiretroviral therapy, the prognosis for people infected with type 1 human immunodeficiency virus (HIV-1) has improved dramatically. However, reports of virologic failure during combination antiretroviral therapy in clinical practice have been as high as 50%. Many factors contribute to virologic failure, such as incomplete adherence, drug resistance, advanced disease at baseline, and poor pharmacokinetic disposition of antiretroviral agents including low plasma levels or inadequate distribution to virally infected cells or compartments.
Two recent studies in patients with suppressed HIV RNA in plasma to fewer than 50 copies/ml demonstrated ongoing viral replication, the source of which may be from virus-containing compartments. An important finding was recovery of drug-sensitive virus from lymph tissue, which suggests drug concentrations are inadequate to suppress replication fully. Insufficient penetration of drugs into certain virus-containing compartments may allow continuing replication and could contribute to virologic failure and development of drug resistance.
Semen is a distinct virus-containing compart-ment that may be isolated from antiretroviral drugs. Virus recovered from semen is frequently genetically different from blood-derived HIV; specifically, they differ in the frequency and pattern of antiretroviral drug-resistant mutations. Combination antiretroviral therapy decreases HIV RNA in semen, but seminal virus may persist despite HIV RNA in plasma of fewer than 50 copies/ml. Moreover, drug-resistant HIV, including resistance to zidovudine, was sexually transmitted presumably through semen. Thus, it is important to understand the disposition of antiretroviral drugs in semen and other virus-containing compartments.
Disposition of antiretroviral drugs in the male genital tract is largely unknown. The presence of tight endothelial capillary cell junctions and cell membrane drug transporters such as P-glycoprotein (collectively called the blood-testis barrier) may prevent penetration of some agents into testicular tissue. Indeed, in rats uptake of a zidovudine bolus by prostate tissue is 91% versus only 18% by testicular tissue. In random semen samples from HIV-infected men, zidovudine was detected in high concentrations relative to serum. Similarly, random measurements of zidovudine and lamivudine showed generally higher levels in semen than in plasma. Timed matched blood plasma and seminal plasma measurements of nevirapine showed a median 60% penetration into semen. In contrast, protease inhibitors appear to penetrate poorly into semen. The objective of this study was to characterize the pharmacokinetic behavior of zidovudine and the main inactive metabolite, its 5¢glucuronide conjugate zidovudine-glucuronide, in the semen of HIV-infected men.
Study Objective. To characterize the concentration-time profiles of zidovudine and zidovudine-glucuronide in semen and serum of men infected with the human immunodeficiency-1 virus (HIV-1).
Design. Open-label observational study.
Setting. University-affiliated teaching hospital and research center.
Patients. Four asymptomatic HIV-1-infected men.
Interventions. Zidovudine administration was followed by an 8-hour intensive pharmacokinetic study on day 1. Over the next 8 days, a dose administration and timed single-sample strategy was employed to determine serum and semen concentration time profiles simultaneously.
Measurements and Main Results. Zidovudine and zidovudine-glucuronide concentrations were uniformly higher in semen than in serum except at 1 hour after the dose. The median area under the curve ratio (semen AUC0-48:serum AUC0-[infinity]) was 3.31 for zidovudine and 15.04 for zidovudine-glucuronide.
Conclusion. Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.
With the advent of combination antiretroviral therapy, the prognosis for people infected with type 1 human immunodeficiency virus (HIV-1) has improved dramatically. However, reports of virologic failure during combination antiretroviral therapy in clinical practice have been as high as 50%. Many factors contribute to virologic failure, such as incomplete adherence, drug resistance, advanced disease at baseline, and poor pharmacokinetic disposition of antiretroviral agents including low plasma levels or inadequate distribution to virally infected cells or compartments.
Two recent studies in patients with suppressed HIV RNA in plasma to fewer than 50 copies/ml demonstrated ongoing viral replication, the source of which may be from virus-containing compartments. An important finding was recovery of drug-sensitive virus from lymph tissue, which suggests drug concentrations are inadequate to suppress replication fully. Insufficient penetration of drugs into certain virus-containing compartments may allow continuing replication and could contribute to virologic failure and development of drug resistance.
Semen is a distinct virus-containing compart-ment that may be isolated from antiretroviral drugs. Virus recovered from semen is frequently genetically different from blood-derived HIV; specifically, they differ in the frequency and pattern of antiretroviral drug-resistant mutations. Combination antiretroviral therapy decreases HIV RNA in semen, but seminal virus may persist despite HIV RNA in plasma of fewer than 50 copies/ml. Moreover, drug-resistant HIV, including resistance to zidovudine, was sexually transmitted presumably through semen. Thus, it is important to understand the disposition of antiretroviral drugs in semen and other virus-containing compartments.
Disposition of antiretroviral drugs in the male genital tract is largely unknown. The presence of tight endothelial capillary cell junctions and cell membrane drug transporters such as P-glycoprotein (collectively called the blood-testis barrier) may prevent penetration of some agents into testicular tissue. Indeed, in rats uptake of a zidovudine bolus by prostate tissue is 91% versus only 18% by testicular tissue. In random semen samples from HIV-infected men, zidovudine was detected in high concentrations relative to serum. Similarly, random measurements of zidovudine and lamivudine showed generally higher levels in semen than in plasma. Timed matched blood plasma and seminal plasma measurements of nevirapine showed a median 60% penetration into semen. In contrast, protease inhibitors appear to penetrate poorly into semen. The objective of this study was to characterize the pharmacokinetic behavior of zidovudine and the main inactive metabolite, its 5¢glucuronide conjugate zidovudine-glucuronide, in the semen of HIV-infected men.