Pharmacokinetic Profile of Progabide, a New γ-Aminobutyric Acid-Mimetic Drug, in Rhesus Monkey

Johno, Ikuo; Ludwick, B. T.

doi:10.1002/jps.2600710609

Cited by 8 publications

(8 citation statements)

References 5 publications

(2 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The intravenous and oral pharmacokinetic parameters of progabide obtained in the present study were in agreement with those measured previously (Johno et al, 1982). Based on the intravenous halflife data, it appears that progabide absorption from an intraperitoneal suspension is dissolution rate limited.…”

Section: Discussionsupporting

confidence: 91%

“…Assuming complete metabolism in the liver and a hepatic blood flow of 2.13 L/h/kg (Forsyth et al, 1968;Branch et al, 1974), the intravenous blood clearance data enable an estimation of the fraction lost by first-pass metabolism from the ratio of clearance and blood flow. The mean pre- dicted bioavailability by a portal route of administration is 34% (Johno et al, 1982). Also, absorption from the intraperitoneal cavity is thought to occur primarily through the portal circulation (Kraft et al, 1968;Lukas et al, 1971).…”

Section: Discussionmentioning

confidence: 99%

“…There were no statistically significant differences in bioavailability between any of these intraperitoneal doses, suggesting no dose dependency in the extent of absorption by the intraperitoneal route in the range of doses examined. [A previous study has shown that the elimination kinetics of progabide are linear (Johno et al, 1982). ]…”

Section: Progabide Single-dose Studiesmentioning

confidence: 99%

“…The rigorous quantification of its efficacy in the alumina gel monkey model is dependent on the development of an optimum dosing regimen. A preliminary investigation of the pharmacokinetic characteristics of progabide in rhesus monkey was conducted (Johno et al, 1982). Its large clearance (one-half of liver blood flow) and low water solubility precluded administration by constant-rate intravenous infusion, which represents the optimum method of administration (Levy et al, 1977a,b; Lockard et al, 1977a,b).…”

mentioning

confidence: 99%

“…In the present study, we investigated the possibility of the administration of a progabide suspension through a chronic intraperitoneal catheter. This approach raised a number of issues with respect to the bioavailability of progabide: (a) Since progabide has a large metabolic clearance (Johno et al, 1982), its absorption from the intraperitoneal cavity may involve a significant first-pass effect, (b) Incomplete bioavailability may also result from dissolution ratelimited absorption from the suspension, (c) Dose and/or time dependency in bioavailability may result from nonlinearity (with respect to dos? and/or time) in any of the above factors.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Disposition of Progabide and Valproic Acid Following Intraperitoneal Administration in Rhesus Monkey

1984

Self Cite

View full text Add to dashboard Cite

The pharmacokinetic characteristics of progabide, a new gamma-aminobutyric acid-mimetic drug, were evaluated following single- and multiple-dose administration of a progabide suspension through a chronic intraperitoneal catheter. Several issues pertaining to the bioavailability of progabide were addressed: first-pass effect, incomplete dissolution, and dose and time dependency. Four male monkeys received five treatments: three intraperitoneal doses (50, 100, and 150 mg), one oral dose (50 mg), and one intravenous bolus dose (150 mg). Bioavailability following intraperitoneal administration was incomplete, consistent with a first-pass effect predicted from intravenous data. There were no significant differences between the absolute bioavailabilities of the three intraperitoneal doses, which ranged between 40 and 49%. The apparent half-life (t 1/2) observed after intraperitoneal administration was significantly longer than the elimination half-life by the intravenous route and tended to increase with dose. This behavior is consistent with dissolution rate-limited absorption. The bioavailability of the suspension administered orally was compared with that of the intraperitoneal route, and no difference was found. However, the apparent t 1/2 by the oral route was significantly longer than that of the intraperitoneal route. In multiple-dosing studies, four different dosing regimens (all intraperitoneal) were examined, including 50 mg every 2 or every 6 h, 20 mg every 2 h, and 40 mg every 4 h. In all these regimens, plasma levels exhibited an accumulation compared with single-dose predictions. Large oscillations in plasma levels were observed when the dosing interval was 6 h and side effects were observed when the dosing interval was 2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Progabide Single-dose Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Disposition of Progabide and Valproic Acid Following Intraperitoneal Administration in Rhesus Monkey

1984

Self Cite

View full text Add to dashboard Cite

show abstract

Latentiation of Chemotherapeutic Agents. Part I: Synthesis of Oxidized Starch Imine Derivatives and Antimalarials

Ferreira¹,

Cruz²,

Korolkovas³

1992

Starch Stärke

View full text Add to dashboard Cite

With the purpose of obtaining animalarial prodrugs, oxidized starch derivatives with antimalarials were prepared. Imines with one drug, sulfonamide or pyrimidine, were synthesized and submitted to usual spectrometric analysis, IR. UV and 1H NMR. With these analysis it was concluded that the following compounds were obtained: derivatives of sulfamethoxazole(ML7), sulfisoxazole(ML8) sulfameter(ML11) and trimethoprim(ML13). Only sulfameter derivative was curative in 100% of mice infected with Plasmodium berghei at 50 mg/weight kg dosis.

show abstract

Submassive hepatic necrosis associated with the use of progabide: A GABA receptor agonist

1988

View full text Add to dashboard Cite

Progabide, a recently introduced gamma-aminobutyric acid mimetic, is currently undergoing clinical evaluation for a variety of convulsive disorders. We describe a patient in whom severe hepatic failure developed after four weeks of Progabide therapy. The patient's course was marked by encephalopathy, jaundice, hypoglycemia, markedly elevated serum aminotransferase levels, and prolongation of the prothrombin time. Liver biopsy showed extensive hepatocellular necrosis. The patient recovered slowly after discontinuation of the drug. The finding of eosinophilia and increased serum IgE suggests an immunologically mediated mechanism for the Progabide-induced hepatic injury. Alternatively, the lipophilic moiety of Progabide may interact with hepatocyte cell membrane lipids leading to toxic injury. We conclude that Progabide may occasionally cause severe hepatic injury.

show abstract

Pharmacokinetic Profile of Progabide, a New γ-Aminobutyric Acid-Mimetic Drug, in Rhesus Monkey

Cited by 8 publications

References 5 publications

Disposition of Progabide and Valproic Acid Following Intraperitoneal Administration in Rhesus Monkey

Disposition of Progabide and Valproic Acid Following Intraperitoneal Administration in Rhesus Monkey

Latentiation of Chemotherapeutic Agents. Part I: Synthesis of Oxidized Starch Imine Derivatives and Antimalarials

Submassive hepatic necrosis associated with the use of progabide: A GABA receptor agonist

Contact Info

Product

Resources

About