These studies investigated the absorption and metabolic conversion of lisdexamfetamine dimesylate (LDX), a prodrug stimulant that requires conversion to d-amphetamine for activity. Oral absorption of LDX was assessed in rat portal and jugular blood, and perfusion of LDX into isolated intestinal segments of anesthetized rats was used to assess regional absorption. Carrier-mediated transport of LDX was investigated in Caco-2 cells and Chinese hamster ovary (CHO) cells expressing human peptide transporter-1 (PEPT1). LDX metabolism was studied in rat and human tissue homogenates and human blood fractions. LDX was approximately10-fold higher in portal blood versus systemic blood. LDX and d-amphetamine were detected in blood following perfusion of the rat small intestine but not the colon. Transport of LDX in Caco-2 cells had permeability apparently similar to cephalexin and was reduced with concurrent PEPT1 inhibitor. Affinity for PEPT1 was also demonstrated in PEPT1-transfected CHO cells. LDX metabolism occurred primarily in whole blood (rat and human), only with red blood cells. Slow hydrolysis in liver and kidney homogenates was probably due to residual blood. The carrier-mediated absorption of intact LDX, likely by the high-capacity PEPT1 transporter, and subsequent metabolism to d-amphetamine in a high-capacity system in blood (ie, red blood cells) may contribute to the consistent, reproducible pharmacokinetic profile of LDX.

Lanthanum carbonate [La2(CO3)3] is a noncalcium, non-aluminum phosphate binder indicated for hyperphosphatemia treatment in end-stage renal disease. A randomized, open-label, parallel-group, phase I study was conducted to determine absolute bioavailability and investigate excretory routes for systemic lanthanum in healthy subjects. Twenty-four male subjects were randomized to a single lanthanum chloride (LaCl3) intravenous infusion (120 microg elemental lanthanum over a 4-hour period), a single 1-g oral dose [chewable La2(CO3)3 tablets; 4 x 250 mg elemental lanthanum], or no treatment (control). Serial blood, urine, and fecal samples were collected for 7 days postdosing. The absolute bioavailability of lanthanum [administered as La2(CO3)3] was extremely low (0.00127% +/- 0.00080%), with individual values in the range of 0.00015% to 0.00224%. Renal clearance was negligible following oral administration (1.36 +/- 1.43 mL/min). Intravenous administration confirmed low renal clearance (0.95 +/- 0.60 mL/min), just 1.7% of total plasma clearance. Fecal lanthanum excretion was not quantifiable after intravenous administration owing to high and variable background fecal lanthanum and constraints on the size of the intravenous dose. These findings demonstrate that lanthanum absorption from the intestinal tract into the systemic circulation is extremely low and that absorbed drug is cleared predominantly by nonrenal mechanisms.

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Lanthanum carbonate is considered to be the most potent of a new generation of noncalcium phosphate binders used to treat hyperphosphataemia in chronic kidney disease (CKD), a condition associated with progressive bone and cardiovascular pathology and a markedly elevated risk of death. Its phosphate-binding action involves ionic binding and precipitation of insoluble complexes within the lumen of the intestine, thereby preventing absorption of dietary phosphate. While pharmacokinetics have little relevance to the efficacy of lanthanum carbonate, they are of fundamental importance when it comes to evaluating safety. When administered as lanthanum carbonate, the oral bioavailability of lanthanum is low (approximately 0.001%). The small absorbed fraction is excreted predominantly in bile, with less than 2% being eliminated by the kidneys. Predictably, therefore, plasma exposure and pharmacokinetics have been shown to be similar in healthy human volunteers and CKD stage 5 patients. With almost complete plasma protein binding, free lanthanum concentrations in patients at steady state are <3 pg/mL. These properties greatly reduce systemic exposure, tissue deposition and the potential for adverse effects. While lanthanum has a variety of calcium-like actions in vitro, there is little or no evidence that these occur in vivo. This paradox is explained by the very low concentrations of circulating free lanthanum ions, which are many orders of magnitude lower than reported effect concentrations in vitro. Safety pharmacology and toxicology evaluations have failed to reveal any significant calcium-like actions in vivo, despite inclusion of high intravenous doses in some cases.Lanthanum carbonate has a low propensity to cause systemic drug interactions due to its poor absorption. However, the higher concentrations present in the gastrointestinal tract can form chelates with some drugs, such as fluoroquinolones, and reduce their absorption. The improved understanding of the pharmacokinetics of lanthanum that has emerged in recent years has helped to explain why the myriad of calcium-like effects described in vitro for lanthanum have little if any relevance in vivo. The pharmacokinetic investigations of lanthanum carbonate formed an important part of the stringent premarketing safety assessment process and have been influential in reassuring both regulators and physicians that the agent can be used safely and effectively in this vulnerable dialysis population.

Guanfacine extended-release formulation demonstrated linear pharmacokinetics. Plasma concentrations and concentration-related pharmacokinetic parameters were higher in children than in adolescents. These differences are likely due to heavier body weights in adolescents and young male subjects. No serious adverse events were reported.