Appearance of Double Peaks in Plasma Concentration–time Profile after Oral Administration Depends on Gastric Emptying Profile and Weight Function

Metsugi, Yukiko; Miyaji, Yoshihiro; Ogawara, Ken Ichi; Higaki, Kazutaka; Kimura, Takeshi

doi:10.1007/s11095-007-9469-z

Cited by 62 publications

(41 citation statements)

References 38 publications

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“…This phenomenon may be explained by the presence of two or more absorption sites in the intestines or irregular gastric emptying. 37,38 Double peaks were also observed in a recent study in which puerarin was administered orally (10 mg/kg) to dogs from tablets. 39 It is not possible to definitively determine the mechanisms responsible for the observed double peak phenomena based on the obtained data, but because this behavior was observed for the oral puerarin suspension as well as for the MEs, it seems unlikely that this phenomenon is caused by the MEs.…”

mentioning

confidence: 54%

Mechanisms of microemulsion enhancing the oral bioavailability of puerarin: comparison between oil-in-water and water-in-oil microemulsions using the single-pass intestinal perfusion method and a chylomicron flow blocking approach

Tang¹,

Hu²,

Liao³

et al. 2013

IJN

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The purpose of the present work was to determine the mechanisms by which microemulsions (MEs) enhance the oral bioavailability of puerarin. The in situ perfusion method was used in rats to study the absorption mechanisms of an oil-in-water (O/W) microemulsion (O/W-ME) and a water-in-oil (W/O) microemulsion (W/O-ME). The possibility of lymphatic transport of the MEs was investigated using a chylomicron flow blocking approach. The results for the absorption mechanisms in the stomach and intestines indicated that the absorption characteristics of the O/W-ME and W/O-ME depend on the segment. The W/O-ME had higher internal membrane permeability than the O/W-ME. The results of the lymphatic transport analyses showed that both the O/W-ME and W/O-ME underwent lymphatic transport and that this pathway was a major contributor to the oral bioavailability of MEs. Furthermore, the type of ME can significantly affect the absorption of puerarin through the lymphatic system due to the oil content and the form of the microemulsion after oral administration. In conclusion, these data indicate that microemulsions are an effective and promising delivery system to enhance the oral bioavailability of poorly water-soluble drugs.

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mentioning

confidence: 54%

Mechanisms of microemulsion enhancing the oral bioavailability of puerarin: comparison between oil-in-water and water-in-oil microemulsions using the single-pass intestinal perfusion method and a chylomicron flow blocking approach

Tang¹,

Hu²,

Liao³

et al. 2013

IJN

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“…This report is the first describing the population PK of metformin in severely obese but nondiabetic children with insulin resistance. Initial analysis of the concentration–time profiles revealed the presence of double peaks, which has been reported with several orally administered drugs and is associated with such factors as gastrointestinal transit time, absorption window effect, irregular gastric emptying, and enterohepatic cycling . We used a 1‐compartment model with 2 absorption sites, one of which has a delayed onset, to describe this double peak phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Effects ofSLC22A1Polymorphisms on Metformin-Induced Reductions in Adiposity and Metformin Pharmacokinetics in Obese Children With Insulin Resistance

Sam

Roza

Hon

et al. 2016

The Journal of Clinical Pharmacology

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Steady state population pharmacokinetics of a non-commercial immediate release metformin (hydrochloride) drug product were characterized in 28 severely obese children with insulin resistance. The concentration-time profiles with double peaks were well described by a one-compartment model with two absorption sites. Mean population apparent clearance (CL/F) was 68.1 L/hr and mean apparent volume of distribution (V/F) was 28.8 L. Body weight was a covariate of CL/F and V/F. Estimated glomerular filtration rate was a significant covariate of CL/F (p<0.001). SLC22A1genotype did not significantly affect metformin pharmacokinetics. The response to 6 months of metformin treatment (HbA1c, HOMA IR, fasting insulin, and glucose changes) was not different between SLC22A1 wild type subjects and carriers of presumably low activity SLC22A1 alleles. However, SLC22A1 variant carriers had smaller reductions in percentage of total trunk fat after metformin therapy, although the percentage reduction in trunk fat was small. The median % change in trunk fat was −2.20 % (−9.00 % – 0.900 %) and −1.20 % (−2.40 % – 7.30 %) for the SLC22A1 wild-type subjects and variant carriers, respectively. Future study is needed to evaluate the effects of SLC22A1 polymorphisms on metformin-mediated weight reduction in obese children.

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“…The appearance of double peaks in plasma C–T profile might be caused by irregular absorption of the eight analytes in the gastrointestinal tract . Possible reasons for the double‐peak phenomenon have been proposed, such as the enterohepatic circulation and the irregular gastric emptying pattern . Other possible explanations of the double peaks included the combination use of herbs and the distribution of the drug in vivo .…”

Section: Resultsmentioning

confidence: 99%

Simultaneous determination of three alkaloids, four ginsenosides and limonin in the plasma of normal and headache rats after oral administration of Wu‐Zhu‐Yu decoction by a novel ultra fast liquid chromatography‐tandem mass spectrometry method: application to a comparative pharmacokinetics and ethological study

Yin

et al. 2013

J. Mass Spectrom.

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A novel, sensitive and reliable ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method has been developed and validated for simultaneous quantitation of eight main active ingredients (evodiamine, rutaecarpine, dehydroevodiamine, limonin, ginsenoside Rb1, Rd, Re and Rg1) in rat plasma after oral administration of Wu-Zhu-Yu (WZY) decoction, which is a celebrated and widely used Traditional Chinese Medicine formula for the treatment of headache. The analytes and internal standard (IS) were separated on a SHIM-PACK XR-ODS II column, and the detection was performed on a UFLC-MS/MS system with turbo ion spray source. The lower limits of quantification were 1.5, 0.5, 1.0, 2.0, 2.0, 1.0, 0.5 and 0.2 ng ml(-1) for evodiamine, rutaecarpine, dehydroevodiamine, limonin, gensenoside Rb1, Rd, Re and Rg1, respectively. Linearity, accuracy, precision and absolute recoveries of the eight analytes were all within satisfaction. The IS-normalized matrix factor was adopted for assessing the matrix effect and accompanied with a satisfactory result. The validated method has been successfully applied to compare pharmacokinetic profiles of the eight active ingredients in rat plasma between normal and headache rats after administration. Exact pharmaceutical effect of WZY decoction on headache was demonstrated by the ethological response of headache rats induced by nitric oxide donor after administration. The results indicated that the absorption of evodiamine, rutaecarpine, gensenoside Rb1, Re and Rg1 in headache group were significantly higher than those in normal group with similar concentration-time curves while no significant differences existed in limonin and ginsenoside Rd between the two groups.

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Appearance of Double Peaks in Plasma Concentration–time Profile after Oral Administration Depends on Gastric Emptying Profile and Weight Function

Abstract: The irregular gastric emptying could be a main reason for the double peaks in plasma concentration profiles. However, the frequency of double-peak occurrence depends on the weight function, particularly the elimination rate, of each drug.

Cited by 62 publications

References 38 publications

Mechanisms of microemulsion enhancing the oral bioavailability of puerarin: comparison between oil-in-water and water-in-oil microemulsions using the single-pass intestinal perfusion method and a chylomicron flow blocking approach

Mechanisms of microemulsion enhancing the oral bioavailability of puerarin: comparison between oil-in-water and water-in-oil microemulsions using the single-pass intestinal perfusion method and a chylomicron flow blocking approach

Effects ofSLC22A1Polymorphisms on Metformin-Induced Reductions in Adiposity and Metformin Pharmacokinetics in Obese Children With Insulin Resistance

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