To determine whether dideoxyinosine is actively transported across the placenta, four pregnant macaques (Macaca nemestrina) near term and their fetuses were infused intravenously in random order with simultaneous doses of dideoxyinosine (42.5 ,ug/min/kg of body weight) and antipyrine (41.7 ,ug/min/kg) for 30 h. The infusions took place after the dams had been chronically catheterized at 128 ± 0.8 days of gestation. In a third infusion, the dams alone received a higher dosage of dideoxyinosine (425 ,ug/min/kg) and the same dosage of antipyrine (41.7 ,ug/min/kg). Samples of maternal and fetal blood and amniotic fluid were collected at intervals for up to 30 h. The concentrations of dideoxyinosine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student's t test. The ratio (mean ± standard deviation) of the steady-state plasma dideoxyinosine concentration in the fetus to that in the dam was 0.49 ± 0.10 at the low dideoxyinosine infusion rate and 0.51 ± 0.00 at the high dideoxyinosine infusion rate. The clearance associated with maternal-fetal transfer of the drug, CLdf (0.38 ± 0.21 ml/min/kg), was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.56 ± 0.27 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.07 ± 0.04 CLdf versus 0.09 ± 0.04 CLfd). Our data indicate that passage of dideoxyinosine across the placenta in pregnant M. nemestrina near term is passive and constant over the dosage range studied.Dideoxyinosine (2',3'-dideoxyinosine; didanosine) is the second dideoxynucleoside to be approved for use in the treatment of AIDS. Although not presently approved for use during pregnancy, dideoxyinosine may be of benefit to pregnant women who cannot tolerate or have become resistant to zidovudine. In addition, data from animal models indicate that dideoxynucleoside therapy of the dam during pregnancy may delay the onset and progression of the disease in offspring infected in utero (15). Thus, information on the extent and mechanisms of transplacental transfer of dideoxynucleosides, including dideoxyinosine, is necessary in the development of therapeutic strategies for the pregnant woman and her potentially infected unborn child. As part of an ongoing series of studies on the dideoxynucleosides, we studied the extent and mechanisms of transfer of dideoxyinosine in vivo across the placenta in a representative nonhuman primate model, Macaca nemestrina.The macaque was chosen because of its anatomical and physiological similarities to humans. It is particularly suitable since it is susceptible to both the simian immunodeficiency virus (12), which produces an AIDS-like syndrome, and the human immunodeficiency virus (1). In addition, the pharmacokinetics of dideoxyinosine in M. nemestrina have been shown to be similar to those in humans (1...
Diltiazem significantly decreased the clearance and increased the t1/2 of quinidine, but quinidine did not alter the kinetics of diltiazem with the dose used. No significant pharmacodynamic interaction was shown for the combination that would not be predicted from individual drug administration.
Since zidovudine and ddI may be used in combination in the future to treat pregnant women who are human immunodeficiency virus positive, we conducted a study to determine whether zidovudine affects the transfer of ddI across the placenta. Zidovudine and ddI were infused simultaneously to three near-term pregnant macaques (Macaca nemestrina) at 156 ؎ 1.5 days of gestation. Samples of maternal and fetal blood and amniotic fluid were drawn at intervals for 30 h. The steady-state dideoxyinosine concentrations in the plasma of the dam (C ssd ), the fetus (C ssf ), and the amniotic fluid (C ssa ) and the ratios C ssf /C ssd and C ssa /C ssf were found to be not significantly different from the values previously determined after the administration of ddI alone during the same pregnancy. We conclude that concurrent zidovudine administration does not affect the transfer of ddI across the placenta in near-term Macaca nemestrina.Clinical trials are being conducted to study the use of combination therapy with ddI (2Ј,3Ј-dideoxyinosine, didanosine) and zidovudine (3Ј-azido-3Ј-deoxythymidine) in the treatment of patients infected with the human immunodeficiency virus (4, 13). The simultaneous or alternate use of these drugs, which have different dose-limiting toxicities, should reduce drug toxicity (13). However, as with any combination therapy, potential drug interactions must also be considered. For example, ddI and zidovudine could conceivably compete at transport sites. Also, since both of these dideoxynucleosides are renally secreted and metabolized (7,8), each could potentially affect the clearance of the other when they are administered in combination. Information on these potential pharmacokinetic interactions is limited. No pharmacokinetic interaction between ddI and zidovudine was found when the drugs were administered in combination intravenously to either rats (21) or pigtailed macaques (Macaca nemestrina) (20). However, Gallo et al. (6) reported a trend (not statistically significant) toward a reduction in both the volume of distribution at steady state and the total clearance of zidovudine when ddI and zidovudine were coadministered to healthy monkeys (Macaca fascicularis). The potential effects of zidovudine on the pharmacokinetics of ddI were not taken into account in the latter study. Since combination therapy with ddI and zidovudine may be offered in the future to pregnant women who are human immunodeficiency virus positive, we investigated as part of an ongoing series of studies on dideoxynucleosides the possibility of a pharmacokinetic interaction between these two drugs, particularly as it may apply to maternal-fetal transfer. The nonhuman primate model was chosen because its placenta is anatomically and physiologically similar to those of humans. The pigtailed macaque is particularly suitable since not only is it susceptible to the simian immunodeficiency virus (14), which produces an AIDS-like syndrome, but it also has been shown to be susceptible to infection with human immunodeficiency virus (1). In a...
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