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Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.

Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.

Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open-label studies were conducted in healthy men: a [...]

Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following [...]

To understand the roles that nucleoside transporters play in the in vivo distribution of clinically important nucleoside analogs, the substrate specificity of each transporter isoform should be determined. In the present work, we studied the substrate specificities of the human and rat orthologs of the [N.sup.+]-dependent purine-selective nucleoside transporter (SPNT; concentrative nucleoside transporter 2), for nucleosides, nucleobases, and base- and ribose-modified nucleoside analogs. The two-electrode voltage-clamp technique in Xenopus laevis oocytes expressing these transporters was used. Purine nucleosides and uridine induced currents in oocytes expressing rat SPNT (rSPNT) or human SPNT1 (hSPNT1). The rank order of magnitude of nucleoside-induced currents was guanosine > uridine > adenosine > inosine and guanosine > uridine > inosine > adenosine for rSPNT- and hSPNT1-expressing oocytes, respectively. Uridine analogs (modified at the 5-position of the base) induced little or no current, suggesting that these compounds are only poorly transported by either transporter. Cladribine induced currents in oocytes expressing rSPNT ([K.sub.0.5] = 57 [+ or -] 12 [micro] M) but not hSPNT1. The ribose-modified nucleoside analogs, adenine arabinoside, and 2',3'-dideoxyadenosine induced currents in rSPNT-expressing, but not in hSPNT1-expressing, oocytes. These data suggest that there are notable species differences in the specificity of SPNT for synthetic nucleoside analogs. two-electrode voltage clamp; concentrative; sodium dependent; guanosine; adenosine

Residues Arg454 and Lys370 of the rat organic anion transporter rOAT3 are necessary for transporting anions. A mutant with Asp454 and Ala370 actually transported cations rather than anions.

A study was conducted to examine the cloning, expression and characterization of the phosphotriesterase homology protein (PHP), an Escherichia coli protein from the phosphotriesterase gene family. PHP was expressed in bacterial cultures prepared on media supporting various metal ions. It was also assayed for enzymatic activity against a panel of nonspecific substrates. Results indicated residues in the metal ligation.

Research shows that sodium-dependent purine nucleoside transporter hSPNT1 exists within the human kidney. Experiments using reverse transcriptase-polymerase chain reactions, northern analysis and homology cloning strategies are described. Genetic analysis demonstrates hSPNT1 gene location at chromosome 15. Genetic sequences representing hSPNT1 are described.

Background and Objective: Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach. Methods: In this analysis, the body weight-based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (θBW&lowbar;CL) and on the central volume of distribution (θBW&lowbar;VI). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [Cmin,] and peak serum concentration [Cmax]) was compared between body weight-based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study. Results: Results from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of θBW&lowbar;CL and θBW&lowbar;VIl in the population pharmacokinetic model are <0.5, fixed dosing results in less variability and less deviation than body weight-based dosing; when both θBW&lowbar;CL and θBW&lowbar;VI are >0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either θBW&lowbar;CL or θBW&lowbar;VI is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (θBW&lowbar;CL and θBW&lowbar;VI <0.5 or ~0.5). The difference of variability in exposure between body weight-based and fixed dosing is generally less than 20% and the percentages of deviation for light and heavy subpopulations are less than 40%. Conclusions: The analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials. [ABSTRACT FROM AUTHOR]

Examines the efficacy of organic anion and cation transporters in physiologic transport. Determination of domains and amino acid residues for organic anion recognition and transport; Mutagenesis of a conserved basic amino acid residue; Role of arginine and lysine in anion specificity.