Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects

Cawello, Willi; Schweer, Horst; Müller, R; Bonn, R.; Seyberth, H. W.

doi:10.1007/bf00192562

Cited by 50 publications

(26 citation statements)

References 9 publications

(11 reference statements)

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“…The rapid increase of plasma concentrations during infusion and the rapid fall post infusion corresponds with the published short terminal half-lives [7,11].…”

Section: Discussionsupporting

confidence: 52%

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Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion.

Cawello

Leonhardt

Schweer

et al. 1995

Brit J Clinical Pharma

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Prostaglandin E1 (PGE1) (30, 60, 120 jig) was administered by intravenous infusion over a 120 min period in an open, three way randomized, cross-over study to 12 healthy male volunteers. For the evaluation of PGEI, PGEo and 15-keto-PGE0, blood samples were drawn prior to, during and after the infusion. Analytical measurements were performed by gas chromatography/negative ion chemical ionization triple stage quadruple mass spectrometry, a highly specific and sensitive GC/MSJMS-method. During intravenous infusion of 30, 60 and 120 jig PGE1, endogenous plasma PGE concentrations increased from 1.7 ± 0.8 to 4.2 ± 1.1, 6.7 ± 1.0 and 11.0 ± 1.9 pg mlrespectively. PGEo plasma concentrations increased from endogenous levels of 1.3 + 1.0 pg ml-' to 7.6 ± 2.1, 14.1 ± 3.7 and 28.0 ± 3.0 pg ml-' respectively, whilst 15-keto-PGE0 plasma concentrations increased from endogenous levels of 10.2 ± 13.9 pg ml-' to 99.3 ± 27.9, 190.4 ± 52.5 and 357.2 ± 72.6 pg ml-' respectively. Within the dose range of 30-120 jg PGEI 2 h-1 there was a linear increase of Cmax and AUC with the dose. The results of the analysis of variance after baseline and dose-correction show a 90% confidence interval in the bioequivalence acceptance range of 80 to 125%.

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“…The rapid increase of plasma concentrations during infusion and the rapid fall post infusion corresponds with the published short terminal half-lives [7,11].…”

Section: Discussionsupporting

confidence: 52%

“…administration of a single dose of PGE, to healthy volunteers [6,7]. The aim of the present study was [1].…”

Section: Introductionmentioning

confidence: 99%

Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion.

Cawello

Leonhardt

Schweer

et al. 1995

Brit J Clinical Pharma

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“…The clinical use of these agents is predicated on certain assumptions about their pharmacokinetics, yet with few exceptions (69) detailed information about the clearance and metabolism of these agents in humans is lacking. Only recently, for example, was exogenous PGE 1 shown to be rapidly converted to circulating 13,14-dihydro-PGE 1 and 15-keto-PGE 1 in humans (70,71). The role of hPGT, if any, in the clearance from the circulation of medicinal PGs can now be approached experimentally by expressing the transporter in vitro and evaluating its interactions with these agents.…”

Section: Discussionmentioning

confidence: 99%

Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT).

Lu¹,

Kanai²,

Bao³

et al. 1996

J. Clin. Invest.

208

138

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We recently identified a cDNA in the rat that encodes a broadly expressed PG transporter (PGT). Because PGs play diverse and important roles in human health and disease, we cloned human PGT (hPGT) from an adult human kidney cDNA library. A consensus sequence (4.0 kb) derived from several clones, plus 3 Ј polymerase chain reaction amplification, exhibited 74% nucleic acid identity and 82% amino acid identity compared to rat PGT. When transiently expressed in HeLa cells, a full-length clone catalyzed the transport of PGE 1 , PGE 2 , PGD 2 , PGF 2 ␣ and, to a lesser degree TXB 2 . Northern blotting revealed mRNA transcripts of many different sizes in adult human heart, placenta, brain, lung, liver, skeletal muscle, pancreas, kidney, spleen, prostate, ovary, small intestine, and colon. hPGT mRNAs are also strongly expressed in human fetal brain, lung, liver, and kidney. The broad tissue distribution and substrate profile of hPGT suggest a role in the transport and/or metabolic clearance of PGs in diverse human tissues. ( J. Clin. Invest.

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“…Cawello et al reported that the plasma elimination of PGE 1 exhibited two phases, that is, their half-lives were 0.2 min and 8.2 min for the a-phase and the b-phase, respectively, in human subjects. 23) However, by using the estimated parameters, the plasma concentration of PGE 1 in the newborn rats was predicted to decline mono-exponentially, and the biological half-life was estimated to be 3 min. Thus, we suggest that the approximate plasma elimination kinetics of PGE 1 can be simply presented by a 1-compartment model in this PRK modeling.…”

Section: Discussionmentioning

confidence: 99%

An Approach to Predict the Ductus-Arteriosus Dilating Effect Induced by Lipo-Prostaglandin E1 in Newborn Rats Lacking Plasma Concentration-Time Data by the Pharmacological Response Kinetic Model.

Yamauchi

Yasunaga

Kawasaki

et al. 2003

Biological & Pharmaceutical Bulletin

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selectively dilate ductus arteriosus in many mammal neonates.1) A cyclodextrin preparation of PGE 1 (PGE 1 -CD)2) and a lipid microsphere preparation of PGE 1 (lipo-PGE 1 ) 3,4) have both been widely used in emergency treatment in neonatal patients with ductus dependent congenital heart diseases (D-CHDs). However, a fatal adverse drug reaction, apnea, may occur when PGE 1 is overdosed.5) Lipo-PGE 1 is a passive targeting-type drug delivery system (DDS) of PGE 1 , in which PGE 1 is dissolved in the lipid emulsion of soybean oil. 6) Momma retorted that the ductus-dilating intensity of lipo-PGE 1 was approximately ten times higher than that of PGE 1 -CD by the clinical monitoring of arterial blood pO 2 in D-CHD patients.3) Thus, lipo-PGE 1 therapy allows for a reduction of the total dose of PGE 1 . Further, the ductus-dilating effect after the discontinuation of lipo-PGE 1 administration lasts much longer than that of PGE 1 -CD. 4,7,8) However, its kinetics have not been clarified from the biopharmaceutical viewpoint. This makes it difficult to present evidence-based precise lipo-PGE 1 therapy in D-CHD patients.Pharmacokinetic analysis based on blood or plasma concentration profiles of drugs has been utilized for optimization of the dosage regimen. Pharmacokinetic/pharmacodynamic (PK/PD) modeling, which is an integrated mathematics model of a pharmacokinetic (concentration-time) and a pharmacodynamic (effect-concentration) event, is a useful tool for predicting the time course of pharmacological response. 9)Ordinary PK/PD modeling studies require validation of both the pharmacokinetic and pharmacodynamic aspects.10) However, it is difficult to obtain both the pharmacokinetic and pharmacodynamic data in, for example, the following cases: as a highly potent drug is administered in quite a low dose, it is difficult to determine plasma concentration of the drug; blood or plasma concentration has no mean in the targetingtype DDS drugs because systemic drug level does not reflect its local pharmacological response. The ductus-dilating effect of PGE 1 has been reported to be extremely potent.1) The clinical dose of lipo-PGE 1 (5 ng/kg/min), a targeting-type DDS, is too low to determine the plasma concentration profiles during the treatment. Thus, in the case of lipo-PGE 1 therapy in D-CHD patients, the acquisition of systemic pharmacokinetic data is technically impossible, and the pharmacokinetic analysis itself is meaningless. In such a case, validation of the model by systemic pharmacokinetic data is impossible, and the only way we can validate the model will be validation by the pharmacological response-time data.In this study, we have assessed changes in the diameter of ductus arteriosus after the bolus i.v. administration of lipo-PGE 1 in a multi-dose study to define a suitable pharmacological response kinetic model (PRK model) and related kinetic parameters. Also, we have investigated whether the model could predict the time course of the ductus-dilating effect under the constant infusion of lipo-PGE 1 . The utility...

show abstract

Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects

Cited by 50 publications

References 9 publications

Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion.

Dose proportional pharmacokinetics of alprostadil (prostaglandin E1) in healthy volunteers following intravenous infusion.

Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT).

An Approach to Predict the Ductus-Arteriosus Dilating Effect Induced by Lipo-Prostaglandin E1 in Newborn Rats Lacking Plasma Concentration-Time Data by the Pharmacological Response Kinetic Model.

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