Statistical comparison of dissolution profiles to predict the bioequivalence of extended release formulations.

Appropriate setting of dissolution specification of extended release (ER) formulations should include precise definition of a multidimensional space of complex definition and interpretation, including limits in dissolution parameters, lag time (t-lag), variability, and goodness of fit. This study aimed to set dissolution specifications of ER by developing drug-specific dissolution profile comparison tests (DPC tests) that are able to detect differences in release profiles between ER formulations that represent a lack of bioequivalence (BE). Dissolution profiles of test formulations were simulated using the Weibull and Hill models. Differential equations based in vivo-in vitro correlation (IVIVC) models were used to simulate plasma concentrations. BE trial simulations were employed to find the formulations likely to be declared bioequivalent and nonbioequivalent (BE space). Customization of DPC tests was made by adjusting the delta of a recently described tolerated difference test (TDT) or the limits of rejection of f2. Drug ka (especially if ka is small), formulation lag time (t-lag), the number of subjects included in the BE studies, and the number of sampled time points in the DPC test were the factors that affected the most these setups of dissolution specifications. Another recently described DPC test, permutation test (PT), showed excellent statistical power. All the formulations declared as similar with PT were also bioequivalent. Similar case-specific studies may support the biowaiving of ER drug formulations based on customized DPC tests.

Mathematical modeling of oral absorption and bioavailability of a fluoroquinolone after its precipitation in the gastrointestinal tract.

The objective was to characterize the in vivo absorption and bioavailability (BA) of a low solubility, high permeability fluoroquinolone (CNV97101) that precipitates in the gastrointestinal (GI) tract by mathematical modeling approach. In situ rat intestinal perfusion studies were performed to characterize the absorption mechanism. The oral fraction absorbed in vivo was lower than the predicted based on the in situ intestinal permeability. Two additional routes of administration, intraduodenal (ID) and intraperitoneal (IP) were investigated to explore if precipitation in stomach and subsequent partial re-dissolution were the causes of the lower in vivo BA. Ex vivo precipitation studies with the stomach content of fasted rats were also carried out. Fitting procedures were performed with NONMEM VII 1.2. The in situ experiments confirmed simultaneous passive and carrier-mediated absorption processes. The ex vivo experiments confirmed precipitation in stomach lowering in vivo the oral fraction absorbed compared with the IP and ID administrations. Due to the almost complete availability of CNV97101 following IP administration, a first hepatic pass could be excluded. The ex vivo assay results and the pharmacokinetic modeling of in vivo data supported the hypothesis of precipitation in the stomach and partial re-dissolution. Nevertheless, other factors such as residence time in the GI may reduce the fraction absorbed even for low oral doses for which re-dissolution was almost complete in vivo.

Influence of polyunsaturated fatty acids on Cortisol transport through MDCK and MDCK-MDR1 cells as blood-brain barrier in vitro model.

Transport across the blood-brain barrier is a relevant factor in the pharmacological action of many drugs and endogenous substances whose action site is located in brain. An overactive P-gp has been suggested to be of relevance for the resistance of the HPA system to be suppressed by glucocorticoids, which is one of the best described biological abnormalities in certain types of depression. PUFA acids have shown clinical efficacy in depressed patients and the hypothesis is that these compounds are able to reduce HPA axis activity as this effect has been shown in animal models of depression. The objective of the present work was (1) to characterize Cortisol transport through MDCK and MDCK-MDR1 cell lines (as in vitro models of the BBB) to confirm its transport mechanism as substrate of P-gp and (2) to evaluate the effect of PUFA acids as enhancers of Cortisol transport in the BBB model and explore the enhancement mechanism. Transport studies of Cortisol were performed in both directions, from apical-to-basolateral and from basolateral-to-apical sides. The in vitro experiments showed that Cortisol transport is concentration dependent and it is affected by several transporters (absorption and secretion processes). The results indicate that PUFA acids increase Cortisol transport in the BBB models but not through the inhibition of P-gp efflux but thanks to membrane fluidification and some effect on tight junction integrity.

A pharmacokinetic model for evaluating the impact of hepatic and intestinal first-pass loss of saquinavir in the rat.

The aim of this study was to quantify the intestinal and hepatic first-pass loss of saquinavir and to assess the effect of coadministration of ritonavir on this first-pass loss. Single doses of 12, 24, and 48 mg of saquinavir and a dose of 24 mg of saquinavir/6 mg of ritonavir were orally, intravenously, or intraperitoneally administered to 94 rats. Ten groups of animals were studied. A semiphysiological pharmacokinetic model incorporating a population pharmacokinetic analysis [nonlinear mixed-effects model (NONMEM)] was developed to analyze plasma concentration-time profiles after administration via each of the three above-mentioned routes. This model confirmed that saturable metabolism in hepatocytes and enterocytes and dose-dependent precipitation in the peritoneal cavity after intraperitoneal administration characterize the pharmacokinetics of SQV. It also demonstrated that low oral bioavailability of saquinavir is due mainly to intestinal rather than to hepatic first-pass metabolism. In addition, it was shown that ritonavir diminished saquinavir clearance through competitive inhibition. The present report presents a new pharmacokinetic model applied in rats to evaluate the impact of hepatic and intestinal first-pass loss on oral bioavailability.

Bioavailability and pharmacokinetic model for ritonavir in the rat.

The aim of this study is to investigate in vivo the oral bioavailability of ritonavir and to evaluate the pharmacokinetic model that best describes the plasma concentration behavior after oral and intravenous administration. Male Wistar rats were intravenously administered at 3 mg dose of pure ritonavir and oral administered at 4.6 +/- 2.5 mg of diluted Norvir. Blood samples were taken by means of the jugular vein for a 24 h period of time. An analytical high-performance liquid chromatography (HPLC) technique was developed in order to quantify ritonavir plasma concentrations. A nonlinear modeling approach was used to estimate the pharmacokinetic parameters of interest. Results showed that a two-compartmental model with zero-order kinetic in the incorporation process of ritonavir into the body better fitted intravenous and oral data. The estimated oral bioavailability by means of noncompartmental and compartmental approaches resulted in 74% and 76.4%, respectively. These values confirm the ones obtained by other authors in the rat. In conclusion, a zero-order kinetic in the incorporation process at the administered doses suggests the saturation of the possible specialized transport mechanisms involved in the incorporation of ritonavir into the body. These results could justify the use of low doses of ritonavir when improving the bioavailability of other protease inhibitors (PIs) is required.

Labetalol absorption kinetics: rat small intestine and colon studies.

Labetalol is a widely used drug for the management of hypertension, which is preferably administered by the oral route despite its low bioavailability. The objective of this study is to ascertain the mechanisms underlying its absorption as an approach to help in predicting the influence of dosage changes, possible drug-drug and drug-fruit juice interactions. Perfusion experiments have been performed in rats in two sites of absorption: the intestine and the colon. The nonlinearity of the process has been established by means of the assay of a wide range of concentrations (2-2000 microM). Fitting of the concentration versus time data allows the estimation of passive diffusion constant in the intestine (1.42 +/- 0.05/h) and the colon (1.13 +/- 0.06/h), V(m) and K(m) of the input process (9.85 +/- 4.98 microM/h, and 10.44 +/- 26.16 microM, respectively) and K(m) of an efflux system (0.53 +/- 1.16 microM) and V(m) in both intestinal segments (2.60 +/- 11.37 microM . /h in the intestine and 0.66 +/- 1.38 microM . /h in the colon). The efflux carrier implicated is identified by means of several inhibition experiments, whose inhibition ability is mathematically estimated. Results suggest the p-glycoprotein as responsible for the efflux of labetalol.

Modelling intestinal absorption of salbutamol sulphate in rats.

The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium between salbutamol sulphate concentrations in lumen and enterocyte, and the salbutamol sulphate absorption was best described by a simultaneous passive diffusion (ka = 0.636 h(-1)) and active absorption (VMax = 0.726 mM/h, Km = 0.540 mM) processes from intestinal lumen to enterocyte, together with an active capacity-limited P-gp efflux (V'max = 0.678 mM/h, K'm = 0.357 mM) from enterocyte to intestinal lumen. The extent of salbutamol sulphate absorption in rat small intestine can be improved by NaN3, grapefruit juice and verapamil.

Use of nonlinear mixed effect modeling for the intestinal absorption data: application to ritonavir in the rat.

The aim of this study is to investigate in situ the mechanisms involved in the gastrointestinal absorption of ritonavir in the rat, as an animal model for preclinical studies of anti-HIV agents in vivo. Four ritonavir solutions (40, 27, 13 and 7 microM) in the presence of 1% dimethylsulfoxide (DMSO) were perfused in the small intestine of anaesthetised rats. Effects of DMSO on the intestinal permeability were investigated using solutions containing antipyrine 1.33 mM and ritonavir 7 microM with and without 1% of DMSO. Antipyrine and ritonavir transport was not modified in the presence of 1% of DMSO. The population pharmacokinetic parameters of the ritonavir intestinal transport were obtained by means of nonlinear mixed effect modelling approach according to a nonlinear absorption and nonlinear secretion. The absorption and secretion kinetic parameters for ritonavir were: Vm=47.6 microM/h; Km=8.77 microM; Vms=3.66 microM/h and Kms=0 microM. The interindividual variability found to ritonavir Vm 13.1%, and the residual variability was 8.98%. The Kms value support the saturation of the carrier at the range of concentrations of ritonavir assayed. The interindividual variability value of the Vm could explain, at least in part, the variability in absorption rate constants observed.

Kinetic modelling of the intestinal transport of sarafloxacin. Studies in situ in rat and in vitro in Caco-2 cells.

The absorption kinetics of sarafloxacin, as a model of fluoroquinolone structure, were studied in the rat small intestine and in Caco-2 cells. The objective of the study was to investigate the mechanistic basis of the drug's intestinal transport in comparison with other members of the fluoroquinolone family and to apply a mathematical modelling approach to the transport process. In the rat small intestine, sarafloxacin showed dual mechanisms of intestinal absorption with a passive diffusional component and an absorptive carrier-mediated component. The characteristics of the animal study design made it suitable for population analysis, thus allowing the accurate estimation of transport parameters and their inter and intra-individual variances. The transport system in the rat model was ATP-dependent, as sodium azide was able to decrease the absorption rate constant in a concentration-dependent fashion. The inhibition mechanism of sodium azide was modelled based on its ATP depletion capacity. The rationale of this approach was to consider the inhibitor-carrier interaction as a concentration- dependent response. This interaction was accurately described by a non-competitive mechanism. In Caco-2 cells, sarafloxacin showed a concentration dependent permeability in both directions apical to basal, and basal to apical. The permeability values and ratios of permeability values at different concentrations suggested the presence of two carriers (absorption and efflux carriers). The passive diffusion component in both systems was compared to that predicted by the absorption-partition correlation, previously established for two series of fluoroquinolones. The discrepancy between the experimental and predicted value suggested the presence of an efflux mechanism similar to that already described for other fluoroquinolones. The differences and similarities of the in situ and the in vitro results are discussed as well as the usefulness of the modelling approach.

Kinetic modelling of passive transport and active efflux of a fluoroquinolone across Caco-2 cells using a compartmental approach in NONMEM.

The purpose was to develop a general mathematical model for estimating passive permeability and efflux transport parameters from in vitro cell culture experiments. The procedure is applicable for linear and non-linear transport of drug with time, <10 or >10% of drug transport, negligible or relevant back flow, and would allow the adequate correction in the case of relevant mass balance problems. A compartmental kinetic approach was used and the transport barriers were described quantitatively in terms of apical and basolateral clearances. The method can be applied when sink conditions are not achieved and it allows the evaluation of the location of the transporter and its binding site. In this work it was possible to demonstrate, from a functional point of view, the higher efflux capacity of the TC7 clone and to identify the apical membrane as the main resistance for the xenobiotic transport. This methodology can be extremely useful as a complementary tool for molecular biology approaches in order to establish meaningful hypotheses about transport mechanisms.

Pharmacokinetic models for the saturable absorption of cefuroxime axetil and saturable elimination of cefuroxime.

Since oligopeptidic drugs such as beta-lactam antibiotics share the same carriers in humans and animals, the absorption and elimination kinetics of cefuroxime (C) were investigated in rats. Plasma C concentrations were measured by liquid chromatography. Pharmacokinetics and bioavailability of C in the rat were examined after intravenous (i.v.) administration at three doses (1.78, 8.9 and 17.8mg) of cefuroxime sodium and oral administration at two doses (2.02 and 8.9mg) of cefuroxime axetil (CA). Preliminary fits using data from intravenous administration of C showed that the drug disposition kinetics were clearly nonlinear, with an increase in plasma clearance as the intravenous dose increased. After oral administration of CA, normalized C(max) was higher for smaller dose than for the largest dose. The population pharmacokinetic parameters were obtained by means of nonlinear mixed effect modelling approach according to a nonlinear elimination and nonlinear absorption two-compartment model. The nonlinear elimination could be attributed to a saturable renal tubular reabsorption of the antibiotic and nonlinear intestinal absorption of CA mediated by carrier system. The oral bioavailability of C, calculated by numeric integration of an amount of CA drug absorbed was 22 and 17% for 2.02 and 8.9mg of prodrug administered orally.

Intestinal transport of cefuroxime axetil in rats: absorption and hydrolysis processes.

Studies were performed using three cefuroxime axetil solutions (11.8, 118 and 200 microM) in three selected intestinal segments and one cefuroxime axetil solution (118 microM) in colon of anaesthetized rats. First-order absorption rate pseudoconstants, k(ap) and effective permeability coefficients, P(eff), were calculated in each set. Absorption of cefuroxime axetil can apparently be described as a carrier-mediated transport, which obeys Michaelis-Menten and first order kinetics in the proximal segment of the small intestine and a passive diffusion mechanism in the mean and distal segments. The absorption kinetic parameters for cefuroxime axetil were obtained: Vm=0.613 (0.440) microM min-1; Km=31.49(28.31) microM and ka=0.011(0.003) min-1. Parameters characterizing degradation of the prodrug were obtained in each intestinal segment: proximal segment k(dp)=0.0049(0.0003) min-1, mean segment, k(dm)=0.0131(0.0007) min-1 and distal segment k(dd)=0.019(0.0009) min-1. Therefore, in situ intestinal absorption of cefuroxime axetil in the proximal segment of the rat in the presence of variable concentrations of cefadroxil has been investigated in order to examine the inhibitory effect of cefadroxil on cefuroxime axetil transport. The data suggest that cefadroxil and cefuroxime axetil share the same intestinal carrier.

The influence of active secretion processes on intestinal absorption of salbutamol in the rat.

Salbutamol was perfused in the small intestine of rat using a standard rat gut "in situ" preparation: (1) in inhibitor-free solution at seven different concentrations (0.15, 0.29, 1.20, 5.0, 9.0, 13.0 and 18.0mM); (2) at a 0.29mM concentration - thought to be close to the allometric dose in man - in the presence of a non-specific enzyme inhibitor, sodium azide (0.3, 3.0 and 6.0mM); and (3) at 0.29mM in the presence of a selective secretion inhibitor, verapamil (10.0 and 20.0mM). In free solution, the mixed-order rate constants, k'(a), of salbutamol increase as the solute concentration increases until an apparent asymptotic value is reached. This could be due to the saturation of enzymatic systems responsible for the secretion of the drug from the enterocyte to the luminal fluid, a process that could explain the poor absorption of salbutamol. In the presence of sodium azide, the k(a) values increased about 1.5-fold, whereas in the presence of verapamil they increased two- to three-fold. These results indicate that salbutamol can act as a substrate of an intestinal secretory transport, which probably includes--at least in part--the enzyme P-glycoprotein, since verapamil has been shown to inhibit this enzyme by dose-dependent competition. This leads to a secretion-limited peroral absorption of salbutamol, which contributes to the poor oral bioavailability of the drug. The possible options for improving salbutamol absorption are discussed.

Pharmacokinetics and absolute bioavailability of oral cefuroxime axetil in the rat.

The objectives of this study were to determine the oral bioavailability of cefuroxime (C) and to evaluate the pharmacokinetic model that best describes the plasma concentration behaviour following single intravenous (IV), intraperitoneal (IP) and oral single doses. The same dose of C was administered by IV, IP and oral routes to three separate groups of rats (2.02 mg of cefuroxime axetil (CA) by the oral route or 1.78 mg of cefuroxime sodium (CNa) by IV and IP route). A two-compartment open model without lag time can predict the C disposition kinetics. The influence of the administration route on the pharmacokinetic parameters and AUC values was investigated by means of a one-way analysis of variance test. The results indicated that the first-pass effect in the intestine and liver reduce oral bioavailability when the drug is administered orally. Cefuroxime bioavailability after oral and IP administration estimated from the plasma levels was nearly 24 and 75%, respectively.

Intestinal absorption kinetics of amiodarone in rat small intestine.

Amiodarone is a widely used antiarrhythmic agent with highly variable therapeutic effects. These seem to be related, at least in part, to the pharmacokinetics of the drug and particularly to some features of its gastrointestinal absorption process. The drug exhibits physico-chemical properties highly suitable for diffusion across lipophilic absorbing membranes, but its low aqueous solubility can act as the rate limiting step for absorption, making the process erratic and variable. In order to gain an insight into the intestinal absorption mechanism of the drug and detect possible non-linearities, a series of experiments using a classical rat gut in situ preparation were carried out with three amiodarone hydrochloride solutions (10, 75, and 200 micrograms mL-1). A synthetic non-ionic surfactant, polysorbate 80, at supramicellar concentration (2 mM) was used as the drug solubilizer. Amiodarone was assayed in biological samples by HPLC using a rapid, sensitive technique that was validated. The amiodarone first-order absorption rate constants obtained in these conditions were similar. No significant differences between ka values were found. Amiodarone absorption was clearly identified as a passive diffusion process.

Nonlinear intestinal absorption kinetics of cefuroxime axetil in rats.

Cefuroxime is commercially available for parenteral administration as a sodium salt and for oral administration as cefuroxime axetil, the 1-(acetoxy)ethyl ester of the drug. Cefuroxime axetil is a prodrug of cefuroxime and has little, if any, antibacterial activity until hydrolyzed in vivo to cefuroxime. In this study, the absorption of cefuroxime axetil in the small intestines of anesthetized rats was investigated in situ, by perfusion at four concentrations (11.8, 5, 118 and 200 microM). Oral absorption of cefuroxime axetil can apparently be described as a specialized transport mechanism which obeys Michaelis-Menten kinetics. Parameters characterizing absorption of prodrug in free solution were obtained: maximum rate of absorption (Vmax) = 289.08 +/- 46.26 microM h-1, and Km = 162.77 +/- 31.17 microM. Cefuroxime axetil transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. On the other hand, the prodrug was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane before absorption occurred. This process reduces the prodrug fraction directly available for absorption. From a bioavailability point of view, therefore, the effects mentioned above can explain the variable and poor bioavailability following oral administration of cefuroxime axetil. Thus, future strategies in oral cefuroxime axetil absorption should focus on increasing the stability of the prodrug in the intestine by modifying the prodrug structure and/or targeting the compound to the absorption site.

Interaction of taurine on baclofen intestinal absorption: a nonlinear mathematical treatment using differential equations to describe kinetic inhibition models.

Previous studies showed that the in situ absorption of baclofen in rat jejunum was inhibited by beta-alanine, a nonessential amino acid, and therefore mediated, at least in part, by some beta-amino acid carrier. In this paper a similar study was undertaken using taurine, a sulfonic beta-amino acid, in order to evaluate its effect and to establish a general inhibition model. To achieve this goal, remaining concentrations of inhibitor were also measured and incorporated into the model. Previously, kinetic absorption in situ parameters for taurine in free solution were obtained: Vm = 27.73 +/- 9.99 mM h-1, K(m) = 8.06 +/- 2.82 mM, Ka (passive difussion component) = 0.40 +/- 0.28 h-1. Isotonic solutions containing 0.5 mM baclofen with starting taurine concentrations ranging from 0 to 100 mM were perfused in rat jejunum, and the remaining concentrations of both compounds were measured. The apparent rate pseudoconstant of the drug clearly decreased as the remaining taurine concentration increased. The interaction can be described as a complete competitive inhibition plus a second component, K, noninhibited, K = 0.58 (+/- 0.03) h-1, Ki = 20.62 (+/- 4.04) mM, Vmi = 28.12 (+/- 6.12) mM h-1, Kmi = 11.71 (+/- 2.53) mM, Kai = 0.47 (+/- 0.10) h-1. A residual absorption of baclofen in the presence of high taurine concentrations was observed, which should be attributed to another transport system not associated with the taurine carrier. In order to elucidate whether or not taurine and beta-alanine carriers are two separate entities that baclofen can use for absorption, further experiments using beta-alanine and taurine together as inhibitors (baclofen, 0.5 mM; beta-alanine, 50 mM, and taurine, 50 mM) were developed. Results indicated that baclofen and both amino acids share the same carrier in the intestinal absorption process. We have completed studies using leucine, taurine, and GABA together as inhibitors of drug absorption. An isotonic perfusion solution of 0.5 mM baclofen in the presence of 50 mM leucine, 25 mM taurine, and 25 mM GABA was perfused. Under these conditions the absorption rate pseudoconstant of baclofen decreases until 0.080 h-1 (+/- 0.069). Practical implications of these phenomena are briefly discussed.

Influence of leucine on intestinal baclofen absorption as a model compound of neutral alpha-aminoacids.

The inhibitory effect of the essential alpha-aminoacid L-leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of an in situ rat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5-100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations however did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component, K = 0.35 (+/- 0.08)h-1, Ki = 0.25 (+/- 0.09)mM, AIC = -97.02. In the light of some of the absorption features of the drug, however, the residual absorption of baclofen in the presence of high leucine concentrations should be attributed to another transport system not used by leucine. Apparent parameters characterizing absorption of leucine in the presence of baclofen (0.5 mM) were Vm = 61.02 (+/- 5.46)mM h-1; Km = 8.04 (+/- 0.89)mM, and AIC = -62.25. The results indicate that baclofen and leucine share some carriers in the intestinal absorption processes. Since leucine is an essential dietary aminoacid, and therefore a normal food component, this finding could be relevant in preventing interactions that would lead to a reduced oral bioavailability during baclofen therapy.

Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium lauryl sulfate as model surfactant: studies in rat duodenum.

The effect of sodium lauryl sulfate (CAS 151-21-3) on the duodenal absorption of cefadroxil (CAS 50370-12-2) has been investigated with the aid of a classical rat gut in situ preparation. Both compounds were entirely compatible in working solutions. Cefadroxil was found to be very stable and only slightly solubilized in the micellar phase. The apparent first-order absorption rate constants for the free antibiotic fraction were determined in free solution, and in the presence of variable surfactant concentration in luminal fluid. A functional interpretation of these data, based both on the law of mass action and the complete noncompetitive transport inhibition equations, showed that the surfactant acts as a nonspecific inhibitor of the carrier-mediated absorption of the antibiotic, but also as an enhancer of its passive absorption component. The net result was an outstanding reduction in the absorption capacity of cefadroxil when it was perfused at 0.1 mg/ml, i.e. far from its carrier saturation (from 3.0 h-1 in free solution to 2.0(-1) at high surfactant concentration, with a minimum of about 1.4 h-1 in the presence of the surfactant at 0.5 mg/mg in duodenal fluid). When cefadroxil was perfused at 10.0 mg/ml, i.e. with its carrier-mediated transport beyond the saturation, the net result was a progressively enhanced absorption (ranging from about 0.9 h-1 in free solution to 2.0 h-1 at high surfactant concentration).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of surfactants on amiodarone intestinal absorption. I. Sodium laurylsulfate.

Amiodarone is a widely used antiarrhythmic agent with high variability in therapeutic effects, which appears to be related, at least in part, to its pharmacokinetics, and in particular, gastrointestinal absorption. The drug exhibits physico-chemical properties highly suitable for diffusion across lipophilic absorbing membranes but its low aqueous solubility can act as the rate limiting step for absorption, making it erratic and variable. In studying the intestinal absorption mechanism of amiodarone, a series of experiments using a rat gut in situ preparation was performed in the presence of a synthetic anionic surfactant, as a drug solubilizer, i.e., sodium laurylsulfate, at variable supramicellar concentrations (from 2.6 to 104 mM). Absorption rate constants of amiodarone decreased as surfactant concentration increased, the absorption being unusually fast at lower surfactant concentrations. Equations were developed to evaluate the relationship between absorption rate constant and surfactant concentration in the intestinal luminal fluid.