The influence of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol in the rat

Hsiao-Hui Chow, D. Lalka

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CL(int)) from 94.1 ± 50.1 to 32.9 ± 11.5 ml/min/kg was observed (p < 0.01 vs. vehicle control). However, a lower dose of vitamin K3 (2 mg/kg in PEG 300) had little effect on this parameter. Interestingly, the PEG 300 vehicle control group exhibited a significantly (p < 0.05) higher CL(int) than that observed in a saline control group (94.1 ± 50.1 vs. 45.9 ± 13.7 ml/min/kg). This difference appeared to be due to an increase in the free fraction of propranolol caused by PEG 300, because in vitro addition of this solvent to serum (at estimated in vivo concentrations) with or without added vitamin K3 doubled propranolol free fraction. Furthermore, rats that received the high dose vitamin K3 (20 mg/kg) treatment exhibited a pronounced increase in the serum concentration of enzymes of hepatic origin (alanine aminotransferase and sorbitol dehydrogenase) and in the incidence of hepatic necrosis. It was also observed that high-dose vitamin K3 treatment caused only minor changes in the urinary recovery of propranolol metabolites. In hepatic microsomal preparations, the in vitro addition of vitamin K3 (80 μM) caused profound inhibition (to <10% of control values) of the formation of both N-dealkylated (desisopropylpropranolol) and ring hydroxylated (4-hydroxypropranolol) metabolites. We conclude that the alteration in the area under the serum concentration-time curve of total drug may be caused by a combination of acute changes in plasma protein binding, acute hepatic injury, and/or inhibition of oxidative metabolism of propranolol. The change in the area under the serum concentration-time curve of free drug is probably only attributable to the last two mechanisms.

Original languageEnglish (US)
Pages (from-to)288-294
Number of pages7
JournalDrug Metabolism and Disposition
Volume20
Issue number2
StatePublished - 1992

Fingerprint

Vitamin K 3
Pharmacokinetics
Metabolism
Propranolol
Rats
Liver
Metabolites
Serum
Alanine Dehydrogenase
L-Iditol 2-Dehydrogenase
Pharmaceutical Preparations
Enzyme inhibition
Control Groups
Hepatic Veins
Wounds and Injuries
Portal Vein
Alanine Transaminase
Protein Binding
Sprague Dawley Rats
Blood Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

The influence of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol in the rat. / Chow, Hsiao-Hui; Lalka, D.

In: Drug Metabolism and Disposition, Vol. 20, No. 2, 1992, p. 288-294.

Research output: Contribution to journalArticle

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abstract = "The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CL(int)) from 94.1 ± 50.1 to 32.9 ± 11.5 ml/min/kg was observed (p < 0.01 vs. vehicle control). However, a lower dose of vitamin K3 (2 mg/kg in PEG 300) had little effect on this parameter. Interestingly, the PEG 300 vehicle control group exhibited a significantly (p < 0.05) higher CL(int) than that observed in a saline control group (94.1 ± 50.1 vs. 45.9 ± 13.7 ml/min/kg). This difference appeared to be due to an increase in the free fraction of propranolol caused by PEG 300, because in vitro addition of this solvent to serum (at estimated in vivo concentrations) with or without added vitamin K3 doubled propranolol free fraction. Furthermore, rats that received the high dose vitamin K3 (20 mg/kg) treatment exhibited a pronounced increase in the serum concentration of enzymes of hepatic origin (alanine aminotransferase and sorbitol dehydrogenase) and in the incidence of hepatic necrosis. It was also observed that high-dose vitamin K3 treatment caused only minor changes in the urinary recovery of propranolol metabolites. In hepatic microsomal preparations, the in vitro addition of vitamin K3 (80 μM) caused profound inhibition (to <10{\%} of control values) of the formation of both N-dealkylated (desisopropylpropranolol) and ring hydroxylated (4-hydroxypropranolol) metabolites. We conclude that the alteration in the area under the serum concentration-time curve of total drug may be caused by a combination of acute changes in plasma protein binding, acute hepatic injury, and/or inhibition of oxidative metabolism of propranolol. The change in the area under the serum concentration-time curve of free drug is probably only attributable to the last two mechanisms.",
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N2 - The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CL(int)) from 94.1 ± 50.1 to 32.9 ± 11.5 ml/min/kg was observed (p < 0.01 vs. vehicle control). However, a lower dose of vitamin K3 (2 mg/kg in PEG 300) had little effect on this parameter. Interestingly, the PEG 300 vehicle control group exhibited a significantly (p < 0.05) higher CL(int) than that observed in a saline control group (94.1 ± 50.1 vs. 45.9 ± 13.7 ml/min/kg). This difference appeared to be due to an increase in the free fraction of propranolol caused by PEG 300, because in vitro addition of this solvent to serum (at estimated in vivo concentrations) with or without added vitamin K3 doubled propranolol free fraction. Furthermore, rats that received the high dose vitamin K3 (20 mg/kg) treatment exhibited a pronounced increase in the serum concentration of enzymes of hepatic origin (alanine aminotransferase and sorbitol dehydrogenase) and in the incidence of hepatic necrosis. It was also observed that high-dose vitamin K3 treatment caused only minor changes in the urinary recovery of propranolol metabolites. In hepatic microsomal preparations, the in vitro addition of vitamin K3 (80 μM) caused profound inhibition (to <10% of control values) of the formation of both N-dealkylated (desisopropylpropranolol) and ring hydroxylated (4-hydroxypropranolol) metabolites. We conclude that the alteration in the area under the serum concentration-time curve of total drug may be caused by a combination of acute changes in plasma protein binding, acute hepatic injury, and/or inhibition of oxidative metabolism of propranolol. The change in the area under the serum concentration-time curve of free drug is probably only attributable to the last two mechanisms.

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