Cheryl L. Zimmerman

Preliminary comparison of sertraline levels in postbariatric surgery patients versus matched nonsurgical cohort.

BACKGROUND Roux-en-Y gastric bypass (RYGB) is the most frequent bariatric procedure performed in the United States, with thousands performed. Because of the changes to the gastrointestinal tract, the potential exists for clinically significant alterations in the absorption/bioavailability of ingested medications. The purpose of the present pilot trial was to determine to what extent RYGB alters the area under the plasma concentration/time curve (AUC(0-10.5)) of the antidepressant, sertraline at a community research center. METHODS After an overnight fast, 5 postbariatric surgery and 5 nonsurgical control subjects matched for body mass index, age, and gender received 100 mg of sertraline. Plasma samples were obtained for 10.5 hours. The mean AUC(0-10.5), maximal plasma concentration, and the interval to the peak plasma level were obtained for both groups. RESULTS The mean AUC(0-10.5) was significantly smaller for the postbariatric surgery group (124.4 ± 55.5 ng-hr/mL, range 62.0-198.1; P = .043) compared with the nonsurgical control group (314.8 ± 129.6 ng-hr/mL, range 194.8-508.7). The maximal plasma concentration was also significantly smaller for the postbariatric surgery group than for the nonsurgical control group (P = .043). CONCLUSION To our knowledge, this is the first reported study exploring antidepressant pharmacokinetics after bariatric surgery. In the present trial, the AUC(0-10.5) and maximal plasma concentration were significantly smaller in the subjects who had undergone RYGB than in the matched subjects who had not. Additional investigation of the effects of bariatric surgery (RYGB, sleeve gastrectomy, and gastric banding) on the antidepressant pharmacokinetic parameters is warranted.

Immediate Consequences of Cigarette Smoking: Rapid Formation of Polycyclic Aromatic Hydrocarbon Diol Epoxides

Polycyclic aromatic hydrocarbons (PAH) are among the likely major causative agents for lung cancer in smokers. PAH require metabolic activation to exert their carcinogenic effects, and one important pathway proceeds through a three-step sequence resulting in the formation of diol epoxides, which react with DNA to produce adducts that can cause mutations and initiate the carcinogenic process. However, no previous published studies have examined this critical pathway in humans specifically exposed to PAH by inhalation of cigarette smoke. This study used a unique approach employing a stable isotope derivative of phenanthrene, the simplest PAH with a bay region, a feature closely associated with PAH carcinogenicity. Twelve subjects each smoked a cigarette to which [D(10)]phenanthrene had been added. Plasma was analyzed for [D(10)]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D(10)]PheT), the major end product of the diol epoxide metabolism pathway of phenanthrene. The analysis was performed by gas chromatography--negative ion chemical ionization--tandem mass spectrometry, using [(13)C(6)]PheT as internal standard. The results demonstrated that the three-step pathway resulting in the formation of diol epoxides, as monitored by [D(10)]PheT, occurred with remarkable rapidity. Levels of [D(10)]PheT in plasma of all subjects were maximal at the earliest time points examined, 15-30 min after smoking the cigarette containing [D(10)]phenanthrene, and decreased thereafter. These results demonstrate that the formation of a PAH diol epoxide occurs rapidly in smokers. Because PAH diol epoxides are mutagenic and carcinogenic, the results clearly demonstrate immediate negative health consequences of smoking, which should serve as a major warning to anyone contemplating initiating tobacco use.

Solubilization of Retinoids by Bile Salt/ Phospholipid Aggregates

AbstractPurpose. The capacity and specificity of bile salt (BS)/phosphatidylcholine (PC) mixed lipid aggregated systems in solubilizing four structurally related retinoids, etretinate, motretinid, fenretinide and N-ethyl retinamide, were determined. Methods. Excess solid drug was dispersed into sodium taurocholate (NaTC)/egg PC systems at lipid ratios of 10:0, 10:2 and 10 mM:10 mM in isotonic HEPES buffer, pH 6.5. A sensitive HPLC method was used to quantify the amount solubilized. The melting point and associated enthalpy change as well as the aqueous solubilities were also measured. Results. The retinoids had aqueous solubilities of less than 25 nM. The predicted aqueous solubility was less than 0.01 nM. The amount of retinoid in 10 mM NaTC was increased from three to four orders of magnitude relative to the aqueous solubility. Further increases in the amount solubilized were observed in the 10:10 mixed micelle dispersion. Fenretinide and N-ethyl retinamide were particularly well solubilized by BS and BS/PC aggregated systems which may be related to the presence of a cyclohexenyl ring. Conclusions. The discrepancy between the observed and predicted aqueous solubility may be due to self-association of the retinoids. Micellar/aqueous distribution ratios appear to be dominated by the hydrophobic effect, although specific interactions also are important. In considering intestinal absorption, the large increase in solubilization with BS/PC micelles would be capable of dramatically increasing the bioavailability in spite of the smaller effective diffusivity of the solubilized retinoid.

Diffusivity of bile salt/phospholipid aggregates in mucin

AbstractPurpose. The objective of this study is to evaluate the effect of the mucous layer on the transport of the drug-solubilizing bile salt/phosphatidylcholine (BS/PC) aggregates. Methods. The self-diffusion coefficient of BS/PC aggregates in bovine submaxillary mucin (BSM) was measured by Fourier-transform pulsed-field gradient spin-echo (FT-PGSE) 1H NMR spectroscopy. Results. In spite of the complexity of the mixture, the FT-PGSE technique allowed the unambiguous determination of the diffusivity of PC and 1H2HO (HDO, natural abundance in D2O). With a series of BS/ PC total lipid concentrations ranging from 1 to 7 g/dl, a progressive decrease in the effective diffusivity of HDO was observed with an increase in the both the BSM and total lipid concentration. The effective diffusivity of PC decreased with increasing lipid concentrations in the presence of mucin, while in the controls it increased. After correcting the effective diffusivity of PC for the obstruction effect of mucin, the size of the BS/PC mixed micelle was assessed. It appears that PC associates with BSM resulting in a decrease in the available PC for micellization. This reduces the average size of the mixed micelle within the mucous layer. Conclusions. The aggregation state of BS/PC micelle is altered by the presence of mucin which would have a direct impact on the transport of dietary lipid and solubilized drug through the aqueous boundary layer of the intestinal tract.

A comparison of duloxetine plasma levels in postbariatric surgery patients versus matched nonsurgical control subjects.

Background Bariatric surgery such as the Roux-en-Y gastric bypass (RYGB) is currently used as a treatment for severe obesity. Alteration of the gastrointestinal tract by this procedure suggests a potential for clinically significant alterations in the bioavailability of ingested medications including antidepressants. Objectives The purpose of this trial was to determine to what extent the RYGB procedure alters the area under the plasma concentration/time curve (AUC0-infinity) of the antidepressant, duloxetine. Methods Ten subjects who were 1 year post-RYGB where compared with healthy control subjects matched for body mass index, age, and sex. Ultrarapid or poor metabolizers for cytochrome P450 2D6 were excluded from the study. Subjects received a single dose of 60 mg of duloxetine. Nineteen plasma samples were obtained during 72 hours to characterize the plasma level profile. Results The mean AUC0-infinity was significantly smaller for the postbariatric surgery (PBS) group (646.74 ng × h/mL [SD, 79.70; range, 539.57–791.62], P = 0.017) compared to the nonsurgical control group (1119.91 ng × h/mL [SD, 593.40; range, 415.5–2426.56]). The Tmax was also significantly shorter for the PBS group (2.2 hours) compared to the nonsurgical control group (6 hours; P = 0.005). No significant difference in Cmax or half-life was identified. Conclusions To our knowledge, this is the first reported study exploring duloxetine pharmacokinetics PBS. This trial found that the bariatric surgery group was exposed to only 57.7% of duloxetine as compared to the nonsurgery group. This finding suggests that clinicians need to monitor patients closely after bariatric surgery and that further exploration of the effects of bariatric surgery on antidepressant pharmacokinetic parameters is warranted.

Antiviral nucleoside drug delivery via amino acid phosphoramidates.

Stable and water soluble amino acid phosphomonoester amidates of AZT were synthesized and shown to have potent anti-HIV-1 activity. Intracellular and cell extract metabolism studies revealed that these compounds are likely to be enzymatically converted to the corresponding monophosphates. In addition, we have shown that the half life and tissue distribution of a phosphoramidate of AZT is 5 and 10-fold greater, respectively, than AZT.

Intestinal Absorption of (–)-Carbovir in the Rat

Abstract(–)-Carbovir (CBV) is a carbocyclic nucleoside analogue with in vitro activity against the human immunodeficiency virus. The sites and mechanism of absorption of (–)-CBV from the rat small intestine were studied in the anesthetized male Sprague–Dawley rat. (–)-CBV was perfused through either duodenal, jejunal, or ileal segments at three concentration levels ranging from 1 to 500 µg/mL. The fraction remaining to be absorbed at steady-state and the absorptive clearance were calculated for each experiment. The effect of solvent drag on the absorptive clearance was also investigated. Two-way ANOVA for the absorptive clearance per unit length was not significant for either (–)-CBV concentration or site of perfusion. The fraction remaining to be absorbed at steady-state was found to be 0.804 ± 0.091 (n = 30). A strong correlation was found between the absorptive clearance and the net water absorptive flux. The mechanism of (–)-CBV absorption across the rat small intestine apparently consists of both passive diffusion and convection.

The Bioavailability and Nonlinear Clearance of (–)-Carbovir in the Rat

The pharmacokinetics and bioavailability of (±)-carbovir, a carbocyclic nucleoside active against human immunodeficiency virus, have been described previously. To determine the bioavailability of (–)-carbovir, the biologically active enantiomer, four male Sprague–Dawley rats received 18 mg/kg of (–)-carbovir through the jugular vein and 54 mg/kg orally. Following the pilot studies, five rats were randomly assigned to receive (–)-carbovir in a three-way crossover design as either a single 18-mg/kg iv bolus, a single 54-mg/kg oral dose, or a single iv infusion of 18 mg/kg to achieve a target steady-state concentration (Css) of 1 µg/ml, the peak concentration after an oral dose. Blood and urine samples were analyzed by an improved ion-paired reversed-phase HPLC method with fluorescence detection. Blood concentrations of (–)-carbovir declined in a biphasic manner after the iv bolus dose. The terminal half-life was 116 and 106 min after the iv bolus and oral dose, respectively. The blood/plasma distribution ratio was approximately 1.0 in the range of 1 to 10 µg/ml of (–)-carbovir in blood. The free fraction in serum was concentration dependent. Significant differences in the renal, nonrenal, and total-body clearances after the iv bolus and iv infusion suggested nonlinear elimination of (–)-carbovir. The oral bioavailabilities derived from blood data were significantly different when the iv bolus was used as a reference rather than the iv infusion. However, the bioavailabilities were not significantly different when the total urinary excretion of unchanged (–)-carbovir after iv bolus or infusion was used as a reference. Concomitant saturation of renal and nonrenal clearances might explain these findings. The oral bioavailability was about 20% at concentrations approximating 1 µg/ml in blood.

Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats

ABSTRACT In vitro studies have demonstrated that water-soluble, nontoxic phosphoramidates of azidothymidine (zidovudine [AZT]) have significant and specific anti-human immunodeficiency virus and anticancer activity. Although polar, these compounds are internalized and processed to the corresponding nucleoside monophosphates. Eight methyl amide and methyl ester phosphoramidate monoesters composed of d- or l-phenylalanine or tryptophan and AZT were synthesized. The plasma stability and protein binding studies were carried out in vitro. Then in vivo pharmacokinetic evaluations of six of the compounds were conducted. Sprague-Dawley rats received each compound by intravenous bolus dose, and serial blood and urine samples were collected. AZT and phosphoramidate concentrations in plasma and urine were quantitated by high-performance liquid chromatography with UV or fluorescence detection. Pharmacokinetic parameters were calculated by standard noncompartmental means. The plasma half-lives of the phosphoramidates were 10- to 20-fold longer than the half-life of AZT. Although the renal clearances of the phosphoramidates were similar to AZT, their total body clearances were significantly greater than that of AZT. The 3- to 15-fold-larger volume of distribution (Vss) for the phosphoramidates relative to AZT appeared to be dependent on the stereochemistry of the amino acid, with the largest values being associated with the l-amino acids. The increased Vss indicates a much greater tissue distribution of the phosphoramidate prodrugs than of AZT. Amino acid phosphoramidate monoesters of AZT have improved pharmacokinetic properties over AZT and significant potential as in vivo pronucleotides.

The Intestinal Absorption of a Prodrug of the mGlu2/3 Receptor Agonist LY354740 is Mediated by PEPT1: In Situ Rat Intestinal Perfusion Studies

LY354740 is a potent mGlu2/3 agonist with a limited oral bioavailability. Its alanyl prodrug, LY544344, showed high affinity to the intestinal peptide transporter PEPT1, and improved the oral bioavailability of LY354740 in various animal models. The aim of the present study was to investigate the mechanism of in vivo absorption of the dipeptidic prodrug LY544344. The permeabilities of LY544344 and LY354740 were examined in the rat in situ single-pass intestinal perfusion model. The intestinal absorptive flux of LY354740 was shown to be very low in comparison with LY544344. The absorptive flux of LY544344 could best be described by a Michaelis-Menten process in parallel with a linear process. The estimated parameters were: J(max) = 26.7 x 10(-5) micromol/(cm(2)-s), K(m) = 2.6 mM. The absorptive permeability of LY544344 was reduced to approximately 5% of control in the presence of excess Gly-Sar, a known PEPT1 substrate. Intracellular accumulation of LY354740 and LY544344, estimated postperfusion, showed high levels of LY354740 over LY544344 at all perfusate concentrations studied. However, there was a decline in the intracellular ratio of LY354740 to LY544344 at higher concentrations, suggesting that the metabolic activation to release LY354740 is saturable.