Oral absorption of anti-acquired immune deficiency syndrome nucleoside analogues. 2. Carrier-mediated intestinal transport of stavudine in rat and rabbit preparations.

The intestinal transport and metabolism of stavudine (d4T), a nucleoside analogue of thymidine used in the treatment of AIDS, was studied using single-pass intestinal perfusion (SPIP), intestinal brush-border membrane vesicles (BBMV), and mucosal homogenates in rats and rabbits. In the SPIP, d4T demonstrated concentration-dependent mean wall permeability (P+/-w) at perfusate concentrations ranging from 0.001 to 25 mM. In coperfusion studies using 0.1 mM thymidine, 1 mM formycin B, or 5 microM NBTI as putative inhibitors of d4T transport, the P+/-w of 5 microM d4T was reduced to 48%, 62%, and 70% of the control value, respectively, suggesting the involvement of multiple nucleoside carriers in the intestinal uptake of d4T. d4T uptake in rat BBMV was significantly greater in the presence of a sodium ion gradient compared with a sodium-free (choline) gradient. The permeability of d4T, in the presence of a sodium gradient, was concentration-dependent and inhibited by 10 mM thymidine but not significantly reduced by 10 mM formycin B. In the presence of 10 microM NBTI, the permeability of d4T was not inhibited; however; the binding of d4T to rat and rabbit BBMV was significantly reduced. Formycin B did not significantly reduce the d4T uptake in rat or rabbit BBMV suggesting that d4T does not interact with the purine-selective N1 nucleoside carrier. However, because formycin B inhibited d4T uptake in the SPIP and since d4T inhibited formycin B uptake in rat but not rabbit BBMV, it appears to interact with the N3 carrier which has been demonstrated in rat but not rabbit intestine. Also, an interaction with the sodium-independent facilitative transporter at the basolateral membrane cannot be ruled out. The low hybrid K(m) and high passive permeability of d4T likely account for the lack of saturable absorption behavior observed in humans, whereas the brush-border and intracellular stability of d4T preserve the high bioavailability observed after oral dosing.

Analysis of intestinal perfusion data for highly permeable drugs using a numerical aqueous resistance--nonlinear regression method.

PURPOSE: To develop, validate and apply a method for analyzing the intestinal perfusion data of highly permeable compounds using the Numerical Aqueous Resistance (NAR) theory and nonlinear regression (NAR-NLR) and to compare the results with the well-established Modified Boundary Layer (MBL) Analysis. METHODS: The NAR-NLR method was validated and the results were compared to the MBL analysis results using previously reported cephradine jejunal perfusion data. Using the Single Pass Intestinal Perfusion (SPIP) method, the concentration dependence of intestinal permeability was investigated for formycin B, proline, and thymidine, three compounds reported to be absorbed by carrier-mediated transport processes. The MBL and NAR-NLR analyses were then applied to the three sets of SPIP data. RESULTS: The results demonstrate that the intrinsic MBL transport parameters were highly variable and, in one case, the analyses failed to give a statistically significant Michaelis constant. The MBL mean dimensionless wall permeabilities (P*w) were greater than the NAR-NLR P*w and were also highly variable. In all cases, the NAR-NLR variability was significantly lower than the MBL variability. The extreme variability in the MBL-calculated P*w is due to the sensitivity of P*w when the fraction of unabsorbed drug (Cm/Co) is low or, alternatively, when P*w approached the aqueous permeability, P*aq. CONCLUSIONS: The NAR-NLR method facilitates the analysis of intestinal perfusion data for highly permeable compounds such as those absorbed by carrier-mediated processes at concentrations below their Km. The method also allows for the use of a wider range of flow conditions than the MBL analysis resulting in more reliable and less variable estimates of intestinal transport parameters as well as intestinal wall permeabilities.

Oral absorption of anti-AIDS nucleoside analogues. 1. Intestinal transport of didanosine in rat and rabbit preparations.

The intestinal transport of didanosine (ddl), a nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection, was characterized using in situ and in vitro techniques. The zero-trans uptake of ddl in rat intestinal brush border membrane vesicles (BBMV) was linear over the range of 1 microM to 50 mM, ruling out a significant carrier-mediated absorption component. The lack of carrier-mediated transport was confirmed in a second species (rabbit). In order to quantitate the convective (Pconv) and diffusive (Pdiff) components of ddl intestinal permeability, the steady state wall permeability (P*w) was determined using an established perfusion technique in rats. Even though baseline P*w (pH 6.5, 290 mosm/kg, no modulator) and fluid absorption results were similar to those of furosemide, the ratios (ddl:furosemide) of Pdiff and phi, the sieving coefficient, were 0.31:1 and 1.70:1, respectively, demonstrating that ddl's Pdiff is low and Pconv is high relative to furosemide's, suggesting significant paracellular absorption of ddl. The apparent diffusive absorptive clearances (P'app) of ddl and furosemide were determined in BBMV, which lack functional tight junctions, and the ratios (ddl:furosemide) of P'app in rat and rabbit were 0.23:1 and 0.24:1, respectively. The BBMV results demonstrate that the majority of ddl intestinal transport does not occur by passive membrane diffusion, confirming the single pass intestinal perfusion (SPIP) findings. The results of these studies suggest that ddl is transported by nonfacilitated membrane and paracellular diffusion with paracellular transport being responsible for the majority of ddl absorption from the intestine.

Pharmacokinetics of pravastatin in elderly versus young men and women.

OBJECTIVE: To assess the effect of age on the pharmacokinetics of pravastatin in men and women. A secondary objective was to evaluate the effect of oral contraceptive steroids on the pharmacokinetics of pravastatin in young women. DESIGN: Open, single-dose study. SETTING: Clinical Pharmacology Unit of Princeton Medical Center for study in men and Hill Top Pharmatest, Cincinnati, for study in women. PARTICIPANTS: Normal, healthy male (aged 19-75 y) and female (aged 18-78 y) volunteers. INTERVENTIONS: Subjects received a single 20-mg dose of pravastatin after an overnight fast. MAIN OUTCOME MEASURES: The maximum plasma pravastatin concentration (Cmax), time required for that concentration to develop (Tmax), and the elimination half-life (beta t1/2). Serum concentrations of pravastatin and its major metabolite, the 3-alpha isomer, SQ 31,906, were determined at 12 intervals from 0.33 to 48 hours after the dose. Urine was collected cumulatively during the same period to determine urinary excretion of pravastatin and SQ 31,906. Both measures were used to determine pharmacokinetic parameters. RESULTS: The pharmacokinetic profiles of pravastatin and SQ 31,906 in young and elderly subjects of men and women differed little. Although the mean area under the concentration time curve of pravastatin was higher in the elderly and significantly higher in the elderly women, Cmax and beta t1/2 values were similar in the young and the elderly volunteers. Concomitant administration of oral contraceptives in young women did not affect the pharmacokinetics of pravastatin or SQ 31,906. CONCLUSIONS: The pharmacokinetics of pravastatin do not necessitate dosage adjustments in elderly men or women. No differences were detected between the disposition of the parent drug or its metabolite in men and women.

Pharmacokinetics, safety, and pharmacologic effects of fosinopril sodium, an angiotensin-converting enzyme inhibitor in healthy subjects.

The pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin-converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril. In a dose-tolerance study (study II), 80 and 160 mg of the drug were administered in doses of 40 mg bid and 80 mg bid for 2 weeks. Pharmacokinetics were determined on days 1 and 14, and blood pressure and ACE activity were measured daily. One hour after all doses of fosinopril, serum ACE activity was undetectable. Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed. ACE activity remained undetectable for more than 24 hours after the treatment was stopped in study II. Serum aldosterone levels were decreased by 50% of baseline values in both studies. In study I, maximal reductions in mean blood pressure occurred approximately 6 hours postdose; once-daily doses of 20 mg or greater achieved reductions of 11.3 to 21.6% (P less than or equal to .05, compared with placebo reductions). Fosinopril was well tolerated. Subjects reported only mild gastrointestinal complications at doses of 80 mg/day or higher. These data show that fosinopril is a safe and effective inhibitor of ACE with a long duration of action on serum ACE activity.