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Purpose: The goal of this study was to develop physiologically based pharmacokinetic (PBPK) models for 2',3'-dideoxyinosine (ddI) in rats when the drug was administered alone (ddI model) and with pentamidine (ddI + pentamidine model), and to use these models to evaluate the effect of our previously reported pentamidine-ddI interaction on tissue ddI exposure in humans., Methods: The PBPK models consisted of pharmacologically relevant tissues (blood, brain, gut, spleen, pancreas, liver, kidney, lymph nodes, muscle) and used the assumptions of perfusion-rate limited tissue distribution and linear tissue binding of ddI. The required physiologic model parameters were obtained from the literature, whereas the pharmacokinetic parameters and the tissue-to-plasma partition coefficients were calculated using plasma and tissue data., Results: The ddI model in rats yielded model-predicted concentration-time profiles that were in close agreement with the experimentally determined profiles after an intravenous ddI dose (5% deviation in plasma and 20% deviation in tissues). The ddI + pentamidine model incorporated the pentamidine-induced increases of ddI partition in pancreas and muscle. The two PBPK models were scaled-up to humans using human physiologic and pharmacokinetic parameters. A comparison of the model-predicted plasma concentration-time profiles with the observed profiles in AIDS patients who often received ddI with pentamidine showed that the ddI model underestimated the terminal half-life (t1/2, beta) by 39% whereas the ddI + pentamidine model yielded identical t1/2, beta and area-under-the-curve as the observed values (< 1% deviation). Simulations of ddI concentration-time profiles in human tissues using the two models showed that pancreas and lymph nodes received about 2- to 30-fold higher ddI concentration than spleen and brain, and that coadministration of pentamidine increased the AUC of ddI in the pancreas by 20%., Conclusions: Data of the present study indicate that the plasma ddI concentration-time profile in patients were better described by the ddI + pentamidine model than by the ddI model, suggesting that the pentamidine-induced changes in tissue distribution of ddI observed in rats may also occur in humans.

Purpose: This study examined the pharmacokinetic interaction between 2',3'-dideoxyinosine (ddI) and pentamidine., Background: ddI and pentamidine are often coadministered to patients with acquired immunodeficiency syndrome, and are both associated with pancreatic toxicity. Information on potential interaction would be useful to assess the need for dose modification and the basis of the higher incidence of pancreatic toxicity associated with coadministration of the two drugs., Methods: ddI (200 mg/kg) and pentamidine (10 mg/kg) were administered by continuous infusion to rats over 3 hr, either alone or concomitantly. Drug analysis was by high pressure liquid chromatography with UV or fluorescence detection, or by radioimmunoassay., Results: Pentamidine coadministration significantly increased the apparent volume of distribution at steady state of ddI from 1.4 to 3.4 l/kg (p = 0.004), and increased the mean residence time from 36.3 to 50.0 min (p = 0.015). Pentamidine enhanced the distribution of ddI from plasma into pancreas (p = 0.001) and muscle (p = 0.026). ddI distribution into spleen and liver was also increased, with differences approaching statistical significance (p = 0.08 and 0.06, respectively). In contrast, ddI coadministration did not affect the total body clearance but increased the urinary excretion and the renal clearance of pentamidine by about 5-fold (p = 0.0003)., Conclusions: These data indicate that pentamidine increased the distribution of ddI into pancreas and muscle, whereas ddI increased the renal elimination of pentamidine.

Purpose: To evaluate the intratracheal route of administration as an alternative to oral administration for 2',3'-dideoxyinosine (ddI)., Methods: A ddI dose (40 mg/kg/300 microliters or 6.5 mg/kg/50 microliters) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 micrograms/kg) of 3H-ddI was administered concomitantly to determine the drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption., Results: ddI was rapidly absorbed from the lungs, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution instilled intratracheally showed that a fraction of the 300 microliters dose spilled over to the gastrointestinal tract, where the entire 50 microliters dose was retained in the lungs. The different distribution of the two doses volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tract after the spillover. Absorption of ddI from the airspace of the lung was biexponential, suggesting two absorption processes., Conclusions: These data indicate significantly higher and less variable bioavailability of ddI by the intratracheal route of delivery compared to the oral route. Furthermore, the complete bioavailability at the lower dose/volume indicates no significant pulmonary first pass elimination for ddI.

Purpose: To use the drug kinetics in dermis to predict the in vivo blood concentration after topical administration., Methods: A two-step pharmacokinetic model was established. The first step was to calculate the drug input rate or flux from the skin to the systemic circulation using the drug kinetic parameters in dermis. These parameters include (a) distance over which the drug concentration declines by 50%, (b) drug concentration at the epidermal-dermal junction, and (c) minimal plateauing drug concentration in the muscle layer. These parameters were experimentally determined from the drug concentration-tissue depth profiles in the dermis, after the application of a topical dose of ddI (200 mg/kg) to rats. The second step was to use the drug input rate together with the systemic disposition pharmacokinetics of ddI in rats to predict the plasma concentration-time profiles. The model-predicted plasma concentration-time profiles were compared with the observed profiles, to determine the validity of the proposed pharmacokinetic model., Results: The observed steady state concentration (CSS) in individual animals (n = 6) deviated from the predicted values by 3 to 55% with 3 of 6 rats showing a < 15% deviation. The mean observed CSS of all animals deviated from the mean predicted values by less than 15%., Conclusions: The close agreement between the observed and the model-predicted drug concentrations indicates that the systemic drug input can be calculated from the drug kinetics in the dermis.

The present study evaluated the kinetics of drug penetration in the dermis. A rat was given a dermal dose of 2',3'-dideoxyinosine (ddI). At 6 hr, the skin tissue was excised, immediately frozen and sectioned, and the decline of drug concentration as a function of tissue depth was determined. The tissue concentration-depth profile showed a semilogarithmic decline, as would be expected in a distributed tissue kinetic model which incorporates diffusion and capillary membrane transport. The goodness of fit of the profiles by the simple diffusion and the distributed models were compared using four statistical criteria, i.e., coefficient of determination. Akaike Information criterion, Schwartz criterion and Imbimbo criterion. These analyses showed that the decline of tissue concentration versus tissue depth in the dermis was better described by the distributed model than by the diffusion model in all 7 animals. To examine the effect of blood perfusion on the tissue concentration-depth profiles, some of the tissues were frozen after 1 and 2 hr storage at room temperature. In contrast to the adjacent tissues frozen immediately, the concentration-depth profiles in tissues frozen after a 1-2 hr delay were described equally well by distributed and diffusion models. A comparison of the concentration-depth profiles in the tissues processed immediately or after a delay showed a 7 fold more shallow slope and a 60% lower concentration at the epidermis-dermis interface after storage. However, storage did not alter the total amount of drug in the entire dermis. Drug degradation during storage was further ruled out by the insignificant ddI degradation in 10% skin homogenate (a half-life of approximately 70 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

The present study examined in rats the concentration-time profiles of 2',3'-dideoxyinosine (ddI) in pharmacologically relevant tissues, including organs where drug effects are desired (brain, lymph nodes, spleen), organs with known drug toxicity (pancreas), and major eliminating organs (liver, kidney). ddI was analyzed by high performance liquid chromatography and radioimmunoassay. In the liver, pancreas, spleen, brain and lymph nodes, the highest concentrations were reached between 4 and 7 min after drug administration. The concentrations subsequently declined in parallel with those in plasma, indicating that plasma and these tissues were in rapid equilibrium. The concentrations in these tissues were less or equal to that of plasma. In the kidney, the maximal concentration occurred at a later time of 14 min, after which concentrations also declined in parallel to those in plasma. The kidney concentrations were about 10-fold greater than plasma concentrations. The ratios of tissue-to-plasma concentrations and of areas under the tissue and plasma concentration-time profiles showed a 230- to 300-fold range with the rank order of kidney >> liver approximately pancreas > lymph nodes > spleen >> brain, with respective values of 10.4, 1.09, 0.90, 0.75, 0.42, and 0.04. These data indicate no accumulation of ddI in brain, lymph nodes, spleen, pancreas and liver, and a significant accumulation in the kidney. The low tissue-to-plasma ratios in brain and spleen and a moderate ratio in lymph nodes indicate that further enhancement of the therapeutic effect of ddI requires improved drug delivery and entrapment in these tissues.

Dideoxynucleosides such as 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) can effectively inhibit the replication of human immunodeficiency virus (HIV) in T lymphoid cells. There is evidence that HIV can infect and replicate in other cells including monocytoid cells and macrophages. The present study compared the antiretroviral activities of ddI and AZT in three lineages of human cells, i.e., MOLT4 (T lymphocytoid, CD4+), U937 (monocytoid, CD4+), and HT1080 (fibroblastoid, CD4-) cells. Feline leukemia virus, a retrovirus that causes immunodeficiency in cats, was used to infect the cells. The drug concentrations needed to reduce the viral p27 antigen titers in cell lysates by 50% (IC50s) were determined. The data show that AZT and ddI inhibited viral replication in all three cell lines. The IC50s of AZT were 0.02, 1.75, and 2.31 microM in MOLT4, HT1080, and U937 cells, respectively. For ddI, the IC50s were 4.31, 9.52, and 43.5 microM, respectively. These data indicate differential antiviral activities of ddI and AZT in the different cells with the following rank order of drug sensitivity: MOLT4 > HT1080 > U937. A study of the intracellular metabolism of [3H]AZT and [3H]ddI shows that the antiretroviral activities of AZT and ddI in the three cell lines correlated with the levels of their intracellular triphosphate metabolites.

This study explored the topical route for administering of 2',3'-dideoxyinosine (ddI), a nucleoside analog used for treating patients with acquired immunodeficiency syndrome. A dose of ddI (approximately 180 mg/kg) dispersed in approximately 1 g ointment base was applied, with or without occlusion, to the back of high follicular density (HFD) and low follicular density (LFD) rats. The systemic ddI clearance was determined using a concomitant administration of an intravenous tracer dose of [3H]ddI. At 24 hr, the experiment was terminated and skin sections at the application site were removed. After topical application, average plateau plasma levels of about 0.6 microgram/ml were achieved within 1 to 2 hr and maintained for 24 hr. Occlusion gave a more uniform plasma profile but did not increase the bioavailability. The systemic bioavailability in HFD and LFD rats was about the same at 33%. In addition, a depot of about 16% of the dose was recovered by rinsing the application area and extracting the drug from the excised application site. These data indicate that about 50% of the dermal dose penetrated the skin barrier in 24 hr. The similar bioavailability in the HFD and LFD rats further suggests an unimportant role for the transfollicular absorption route for ddI. The effect of a mixture of penetration enhancers, Azone and propylene glycol (5:95), was studied in HFD rats. Coadministration of ddI with the enhancers did not increase the ddI bioavailability. However pretreatment and coadministration with the enhancers significantly increased the bioavailability to 62%, which is a conservative estimate because the plasma drug level was still at a plateau when the experiment was terminated at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

This study explored the rectal route of administration for 2',3'-dideoxyinosine (ddI). Rats were given a rectal infusion of nonradiolabeled ddI (200 mg/kg in 0.7 mL saline) over 35 min along with an intravenous (iv) bolus injection of [8-(3)H]ddI (20 microCi, equivalent to 2.1 micrograms), which was used to calculate the absolute rectal bioavailability of ddI. Maximal plasma concentrations of rectally administered unlabeled ddI were 5.4 +/- 2.2 micrograms/mL and were reached at the end of the infusion. The rectal bioavailability averaged 15.6 +/- 4.4% (n = 9). The second aim of this study was to examine the kinetics of ddI absorption from the colorectal region. Analyses of the absorption rate-time profiles by the Loo-Riegelman and deconvolution methods showed biphasic absorption: a rapid phase during infusion and a slow phase postinfusion. These profiles were inconsistent with a mammillary model with absorption from a single site with one apparent rate constant. The model which gave the best fit for infusion and postinfusion data consisted of two different sites (colon and rectum) with different apparent absorption rate constants. The two sites were connected by a first-order transfer of drug solution from rectum to colon. The apparent absorption rate constant in the rectum was 39-fold higher than that in the colon. In conclusion, these results show absorption of ddI from the colorectal region and suggest the rectal route as an alternative to the oral route. The data further suggest different absorption sites in the colorectal region, with a more rapid absorption in the rectum than in the colon.

We previously reported a > 80% presystemic loss of 2',3'-dideoxyinosine (ddl) in rats after an oral dose. The present study investigated the extent of drug loss due to incomplete absorption and presystemic elimination by intestinal wall, liver and intestinal microflora. In vitro metabolism by tissue homogenates showed that the extraction by liver, duodenum, jejunum and ileum was 19.0, 0.5, 1.8 and 1.4%, respectively. Hence, metabolism by the intestinal wall contributed less to the first-pass metabolism than the liver. The in vivo first-pass elimination was determined by infusing ddl into the liver and different parts of the intestinal tract. The in vivo extractions of 12 and 200 mg kg-1 of ddl doses by the liver were 23 and 5%, indicating a concentration-dependent liver metabolism. The in vivo liver extraction at the low dose was similar to the in vitro extraction. The in vivo extraction was 10% in the duodenum and 73% in the ileum. The significantly higher in vivo intestinal extractions compared to the in vitro extractions indicate a loss due to factors in addition to intestinal wall enzyme metabolism. Incomplete absorption was ruled out, based on the undetectable excretion of ddl in feces after duodenal or ileal infusion. A 14% w/v solution of intestinal contents degraded ddl by 18 and 38% over 2 and 24 hr, respectively, at 37 degrees C. By linear extrapolation, a 100% w/v enzyme solution would degrade the entire dose within 1.5 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses. ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phosphorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.

We investigated the pharmacokinetic interaction between 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI), given to rats by intravenous injection. For both compounds, the clearances, terminal half-lives, and fractions of the dose excreted unchanged in urine were not altered by the other drug (P greater than 0.05), indicating no pharmacokinetic interaction between the two drugs.

A high-performance liquid chromatographic analysis for the anti-AIDS drug 2',3'-dideoxyinosine (ddI) in rat plasma and urine, with a limit of detection of 0.2 microgram/ml and requiring a sample size of 100 microliters is described. Diluted plasma or urine samples were extracted using a C18 solid-phase extraction column. Retention of ddI on more polar solid-phase extraction columns was insufficient for sample clean-up. This method is useful for pharmacokinetic studies of ddI in small rodents.