The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of zidovudine.
OBJECTIVE
Zidovudine remains part of combination antiretroviral therapy. Pharmacological studies rely on quantitation of active triphosphates in peripheral blood mononuclear cells. This study evaluated the impact of female sex and contraceptive therapy on zidovudine plasma and intracellular pharmacokinetics and the impact of contraceptive therapy on HIV viral load.


METHODS
Serial plasma and intracellular zidovudine pharmacokinetics following oral and intravenous dosing were determined in 18 men and 20 women treated with zidovudine. Women could repeat pharmacokinetics assessment following 2 months oral or injectable contraceptive therapy. Zidovudine plasma and intracellular mono-, di- and triphosphate concentrations were determined by liquid chromatography tandem mass spectrometry. Plasma and cervical viral loads were determined preceding and following 2 months of contraceptive therapy in women.


RESULTS
Men exhibited higher area under the concentration versus time curve for intracellular zidovudine and zidovudine-monophosphate following oral and intravenous dosing and higher zidovudine triphosphate following oral dosing. There was no difference between men and women in plasma zidovudine parameters. Furthermore, contraceptive therapy had no effect on zidovudine plasma or intracellular pharmacokinetics or on plasma or cervical HIV-1 RNA levels.


CONCLUSIONS
Using an optimized pharmacokinetic design, this study indicated men exhibit significantly higher zidovudine-monophosphate and zidovudine-triphosphate exposure following zidovudine oral administration, having implications for drug toxicity and overall tolerance of zidovudine therapy. The lack of an effect of contraceptive therapy on zidovudine pharmacokinetics is surprising in light of previous pharmacokinetic studies for drugs eliminated primarily through glucuronidation. Contraceptive therapy had no effect on plasma or cervical viral load, results consistent with previous findings.
Aweeka
Francesca T
FT
Drug Research Unit, University of California, San Francisco, California 94143-0622, USA. faweeka@sfghsom.ucsf.edu
Rosenkranz
Susan L
SL
Segal
Yoninah
Y
Coombs
Robert W
RW
Bardeguez
Arlene
A
Thevanayagam
Lourdes
L
Lizak
Patricia
P
Aberg
Judith
J
Watts
D Heather
DH
D000284:Administration, Oral; D000328:Adult; D003271:Contraceptive Agents, Female / Q000008:administration & dosage*; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006679:HIV Seropositivity / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D008656:Mestranol / Q000008:administration & dosage; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage; D012367:RNA, Viral / Q000032:analysis; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012737:Sex Factors; D019562:Viral Load; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D003271:Contraceptive Agents, Female; D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; C014715:Norinyl; D008656:Mestranol; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone