The influence of gastrointestinal transit on drug absorption in healthy volunteers.

Riley, S A; Sutcliffe, Frances; Kim, M; Kapás, Margit; Rowland, Malcolm; Turnberg, L A

doi:10.1111/j.1365-2125.1992.tb04104.x

Cited by 30 publications

(18 citation statements)

References 42 publications

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“…There is some information on the effect of gastric emptying on alcohol absorption but less is known of inter-and intra-subject variability of intestinal transit time and portal blood flow [29].…”

Section: Discussionmentioning

confidence: 99%

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Inter‐individual and intra‐individual variability of ethanol concentration‐time profiles: comparison of ethanol ingestion before or after an evening meal.

Fraser

Rosalki

Gamble

et al. 1995

Brit J Clinical Pharma

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1. The magnitude of the variability of ethanol absorption is an important factor for studies that seek to determine the significance of potential interactions between ethanol and drugs. The aim of this study was to determine the extent of inter‐ and intra‐individual variability of ethanol concentration‐time profiles in fasted and fed subjects. 2. Twenty‐four healthy male subjects were randomized to receive ethanol 0.3 g kg‐1 before an evening meal on two study days and ethanol 0.3 g kg‐1 after an evening meal on two study days. Plasma ethanol concentrations were measured at intervals from 0‐240 min. 3. There were significant differences in the mean area under the ethanol concentration‐time curve (AUC), the mean peak ethanol concentration (Cmax), the mean ethanol elimination slope and the time to peak ethanol concentration between the fed and fasted subjects. There were no significant differences between the first and second study days for either fed or fasting subjects for all parameters. 4. There was no statistically significant difference in inter‐ or intra‐subject variance between fed and fasted studies although the coefficients of variation (standard deviation expressed as a percentage of the mean) for the differences between the first and second study day were higher for fed studies. 5. The large inter‐ and intra‐individual variability of alcohol absorption for both fasted and fed subjects must be considered in the design of alcohol‐drug interaction studies.

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Section: Discussionmentioning

confidence: 99%

“…Great inter-and intra-subject variability in gastric emptying has been demonstrated even with a strictly standardized protocol of meals [19,29,31]. Gastric emptying has a marked effect on absorption of most drugs because it governs the access of the drug to the main absorptive surface, the small intestine [32].…”

Section: Discussionmentioning

confidence: 99%

Inter‐individual and intra‐individual variability of ethanol concentration‐time profiles: comparison of ethanol ingestion before or after an evening meal.

Fraser

Rosalki

Gamble

et al. 1995

Brit J Clinical Pharma

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“…of 17.8 min for the 60 ml volume. The mean t 50% values of unfed monkeys for both liquid volumes were similar to those of fasting humans, exhibiting a range of 10-30 min [2][3][4][5]. Additionally, there was no significant difference in the t 50% values between 2 liquid volumes for these 7 monkeys, and the coefficients of variance of 40.1% for the 20-ml oral dose and of 64.7% for the 60-ml oral dose were much smaller than those calculated from data taken on all 10 monkeys.…”

Section: Gastric Emptying Rate Of Liquids In Unfed Monkeysmentioning

confidence: 96%

Gastrointestinal transit of liquids in unfed cynomolgus monkeys

Kondo¹,

Takahashi²,

Watanabe³

et al. 2003

Biopharm & Drug Disp

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In this study, the gastric emptying rate and oro-caecal transit time of two liquid volumes (20 and 60 ml) were compared in unfed cynomolgus monkeys. First, the acetaminophen method was used to determine the gastric half-emptying time (t(50%)). The mean t(50%) from seven monkeys was 21.2 min for the 20-ml volume and 27.8 min for the 60-ml volume. This mean t(50%) in monkeys is similar to that reported previously in fasting humans. Next, the sulfasalazine-sulfapyridine method was used to determine median oro-caecal transit times for the 2 liquid volumes; these times were 2.5 h for the 20-ml volume and 2.3 h for the 60-ml volume, which are about 1.5 h shorter than previously reported transit times in humans. An increase in volume administered did not significantly change either the t(50%) or oro-caecal transit time. The data also show that variability in both t(50%) and oro-caecal transit time within each monkey is not as great as the large variability between monkeys. Consequently, cynomolgus monkeys are good model animals to use for studies on the gastric emptying of drug-containing liquids after fasting; however, analysis of results from bioavailability studies must compensate for differences in the oro-caecal transit time between monkeys and humans.

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“…The exact dose at which saturation occurs for a given patient is presumably a function of the level of expression of the gabapentin transport system in the intestine. For drugs that are exclusively absorbed in a narrow window of the small intestine, large interpatient variability in the rate of transit through the small intestine leads to additional variability in the extent of absorption (Birkebaek et al, 1990;Riley et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: II. Improved Oral Bioavailability, Dose Proportionality, and Colonic Absorption Compared with Gabapentin in Rats and Monkeys

Cundy¹,

Annamalai²,

Bu³

et al. 2004

J Pharmacol Exp Ther

119

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The absorption of gabapentin (Neurontin) is dose-dependent and variable between patients. Rapid clearance of the drug necessitates dosing three or more times per day to maintain therapeutic levels. These deficiencies appear to result from the low capacity, limited intestinal distribution, and variable expression of the solute transporter responsible for gabapentin absorption. Saturation of this transporter at doses used clinically leads to unpredictable drug exposure and potentially ineffective therapy in some patients. XP13512 [(Ϯ)-1-([(␣-isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed by highcapacity nutrient transporters located throughout the intestine. XP13512 was efficiently absorbed and rapidly converted to gabapentin after oral dosing in rats and monkeys. Exposure to gabapentin was proportional to prodrug dose, whereas exposure to intact XP13512 was low. In rats, Ͼ95% of an oral dose of 14 C-XP13512 was excreted in urine in 24 h as gabapentin. In monkeys, oral bioavailability of gabapentin from XP13512 capsules was 84.2% compared with 25.4% after a similar oral Neurontin dose. Compared with intracolonic gabapentin, intracolonic XP13512 gave a 17-fold higher gabapentin exposure in rats and 34-fold higher in monkeys. XP13512 may therefore be incorporated into a sustained release formulation to provide extended gabapentin exposure. XP13512 demonstrated improved gabapentin bioavailability, increased dose proportionality, and enhanced colonic absorption. In clinical use, XP13512 may improve the treatment of neuropathic pain, epilepsy, and numerous other conditions by increasing efficacy, reducing interpatient variability, and decreasing frequency of dosing.Gabapentin (Fig. 1) (Kelly, 1998). Its efficacy in neuropathic pain and epilepsy may involve binding of the drug to the ␣ 2 ␦ subunit of a voltage-dependent calcium channel (Gee et al., 1996;Marais et al., 2001).The clinical pharmacokinetics of gabapentin have been studied in healthy volunteers and patients with epilepsy (McLean, 1995;Gidal et al., 1998Gidal et al., , 2000Boyd et al., 1999). Gabapentin bioavailability is dose-dependent, decreasing from an average of about 60% at a 300-mg dose to about 35% or less at doses used to treat neuropathic pain. The underlyArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.067959. ABBREVIATIONS: XP13512, (Ϯ)-1-([(␣-isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid; SMVT, sodium-dependent multivitamin transporter; MCT-1, monocarboxylate transporter type 1; HPLC, high-pressure liquid chromatography; GP, gabapentin; LC/MS/MS, liquid chromatography-tandem mass spectrometry; CSF, cerebrospinal fluid; t 1/2 , elimination half-life; T max , time to maximum concentration; AUC (0-inf) , area under the concentration versus time curve extrapolated to infinity; AUC, area under the curve.

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The influence of gastrointestinal transit on drug absorption in healthy volunteers.

Cited by 30 publications

References 42 publications

Inter‐individual and intra‐individual variability of ethanol concentration‐time profiles: comparison of ethanol ingestion before or after an evening meal.

Inter‐individual and intra‐individual variability of ethanol concentration‐time profiles: comparison of ethanol ingestion before or after an evening meal.

Gastrointestinal transit of liquids in unfed cynomolgus monkeys

XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: II. Improved Oral Bioavailability, Dose Proportionality, and Colonic Absorption Compared with Gabapentin in Rats and Monkeys

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