Lubiprostone

Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion.

By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium.

Lubiprostone, via activation of apical ClC-2 channels in intestinal epithelial cells, bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability.

Activation of ClC-2 by lubiprostone has also been shown to stimulate recovery of mucosal barrier function and reduce intestinal permeability via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.

Although the pharmacologic effects of lubiprostone in humans have not been fully evaluated, animal studies have shown that oral administration of lubiprostone increases chloride ion transport into the intestinal lumen, enhances fluid secretion into the bowels, and improves fecal transit.

Following oral administration, concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C_max), and half-life (t_½) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized.

Absorption

Peak plasma concentrations of M3, after a single oral dose of 24 mcg of lubiprostone, occurred at approximately 1.1 hours. The C_max was 41.5 pg/mL and the mean AUC_0–t was 57.1 pg∙hr/mL. The AUC_0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone (6-times the maximum recommended 24 mcg dose).

Food Effect

A study was conducted with a single 72-mcg dose of ³H-labeled lubiprostone (3-times the maximum recommended 24 mcg dose) to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that C_max decreased by 55% while AUC_0–∞ was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials.

Distribution

In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins.

Elimination

Metabolism

Lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. Further in vitro studies indicate that M3, a metabolite of lubiprostone, is formed by the reduction of the 15-carbonyl moiety to a hydroxy moiety by microsomal carbonyl reductase. M3 makes up less than 10% of the dose of radiolabeled lubiprostone.

Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption.

Excretion

Lubiprostone could not be detected in plasma; however, M3 has a t_½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of ³H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces.

Specific Populations

Male and Female Patients

The pharmacokinetics of M3 were similar between male and female subjects.

Patients with Renal Impairment

Sixteen subjects, 34 to 47 years old (8 severe renally impaired subjects [creatinine clearance (CrCl) less than 20 mL/min] who required hemodialysis and 8 control subjects with normal renal function [CrCl above 80 mL/min]), received a single oral 24-mcg dose of lubiprostone. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL). Plasma concentrations of M3 were within the range of exposure from previous clinical experience with lubiprostone.

Patients with Hepatic Impairment

Twenty-five subjects, 38 to 78 years old (9 with severe hepatic impairment [Child-Pugh Class C], 8 with moderate impairment [Child-Pugh Class B], and 8 with normal liver function), received either 12 mcg or 24 mcg of lubiprostone under fasting conditions. Following administration, lubiprostone plasma concentrations were below the limit of quantitation (10 pg/mL) except for two subjects. In moderately and severely impaired subjects, the C_max and AUC_0–t of the active lubiprostone metabolite M3 were increased, as shown in the following table.

Pharmacokinetic Parameters of the Metabolite M3 for Subjects with Normal or Impaired Liver Function following Dosing with lubiprostone:

These results demonstrate that there is a correlation between increased exposure of M3 and severity of hepatic impairment.

Drug Interaction Studies

Based upon the results of in vitro human microsome studies, there is low likelihood of pharmacokinetic drug–drug interactions with lubiprostone. Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone. Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.