The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D5W or D5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH < 2.0) prior to administration of ranitidine and increased gastric pH (pH > 6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 microM) with only 4/30 levels detectable after D5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D5W pretreatment (P < 0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH.

Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection.

Polysulfated polysaccharides are attractive candidates for antiviral drug development because of their potent in vitro activities against human immunodeficiency virus (HIV), herpesviruses, and other enveloped viruses. To determine the potential anti-HIV activity of a prototypical polysulfated polysaccharide, we administered the maximally tolerated dose of dextran sulfate by continuous intravenous infusion to 10 subjects with symptomatic HIV infection for up to 14 days. Since parenteral dextran sulfate is an anticoagulant, the infusion was adjusted to produce the greatest acceptable increase in activated partial thromboplastin time. Drug concentrations in plasma achieved with this protocol were up to 200-fold greater than the 50% inhibitory concentration for free HIV infectivity in vitro. Despite this, circulating HIV antigen (p24) levels increased in all eight subjects who received the drug for more than 3 days (median proportional increase, 73.5%; range, 32 to 130%); this increase was highly significant when it was compared with that in a large cohort of untreated historical controls (Fisher's exact test, P less than 0.001). Frequent decreases in infusion rate were required in all subjects to maintain a constant activated partial thromboplastin time; plasma dextran sulfate levels did not fall as the infusion rate decreased, suggesting a decline in estimated drug clearance over time. Continuous intravenous dextran sulfate was toxic, producing profound but reversible thrombocytopenia in all eight subjects who received drug for more than 3 days and extensive but reversible alopecia in five of these subjects. Because of its toxicity and lack of beneficial effect on surrogate markers, dextran sulfate is unlikely to have a practical role in the treatment of symptomatic HIV infection.

Probenecid and zidovudine metabolism.

The effects of probenecid, a known inhibitor of glucuronidation, on the pharmacokinetics of zidovudine were assessed in eight subjects receiving zidovudine as treatment for human immunodeficiency virus infection. Zidovudine plasma concentrations were measured while subjects were receiving zidovudine alone, after 3 days of zidovudine plus 500 mg probenecid every 8 h, and after 3 days of zidovudine plus 500 mg probenecid plus 260 mg quinine sulphate every 8 h. A median increase of 80% in the area under the zidovudine plasma concentration/time curve occurred with the addition of probenecid. Quinine sulphate prevented the probenecid effect but had no effect on zidovudine kinetics when taken without probenecid by four other subjects. All of the effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine changed the renal elimination of zidovudine. Probenecid could be used in combination with zidovudine to extend the interval between doses and reduce the daily requirement for zidovudine, thus enhancing convenience and reducing costs.