Biomedical subjects

A Küpfer

Publications and source records attributed to A Küpfer.

62 records · Page 4Linked to original sources

PubMed1978

Hepatic metabolism of aminopyrine in patients with chronic renal failure.

1. To evaluate potential alterations in hepatic metabolism of drugs occurring in patients with renal insufficiency the fate of aminopyrine was studied in 17 patients with chronic renal failure and in 27 normal subjects. 2. Although patients with chronic renal failure exhibited large variations, their aminopyrine plasma disappearance times (mean 0.62 +/- SD 0.24 h-1) were significantly higher than those found in normal subjects (0.30 +/- 0.07 h-1, P less than 0.002). 3. 14CO2 derived from [dimethylamine-14C]aminopyrine disappeared from breath more rapidly in patients with chronic renal failure and a history of analgesic abuse (0.40 +/- 0.04 h-1) than in control subjects (0.22 +/- 0.03 h-1, P less than 0.01) and in other patients with chronic renal failure (0.24 +/- 0.04 h-1). 4. Dialysis treatment and serum creatinine concentrations were not correlated with the rates of aminopyrine metabolism. Two additional patients, however, with combined renal and hepatic disease, exhibited markedly slowed rates of aminopyrine demethylation. 5. Although chronic renal failure by itself might not alter microsomal drug metabolism it is concluded that, in patients with a history of abuse of phenacetin-containing analgesics, marked acceleration in aminopyrine N-demethylation may be observed.

Adult↗

PubMed1978

Polymorphic acetylation and aminopyrine demethylation in Gilbert's syndrome.

Polymorphic acetylation was investigated in twenty-seven patients with Gilbert's syndrome using the sulphadimidine test. Whereas the finding of 51% slow acetylators in seventy-eight control persons agreed well with the expected frequency in a continental European population, the prevalence of slow acetylators in Gilbert's syndrome was increased to 78% (P less than 0.03, Woolf's G-test). After oral administration of 14C-aminopyrine there was no significant difference between seventeen patients with Gilbert's syndrome and twenty-seven normal controls in total plasma clearance of aminopyrine (280 +/- SD 100 and 270 +/- 60 ml/min) and in the disappearance curve of 14CO2 in breath (0.23 +/- 0.04 and 0.22 +/- 0.03 h-1, respectively). Thus, whereas aminopyrine metabolism appears unaffected in the examined patients, the data documents a new association between slow acetylator status and Gilbert's syndrome.

Acetylation↗

PubMed1977

Stereoselective metabolism, pharmacokinetics and biliary elimination of phenylethylhydantoin (Nirvanol) in the dog.

The influence of stereoisomerism on pharmacokinetics and rates of hepatic drug metabolism was investigated in four dogs using the enantiomers of phenylethylhydantoin (PEH) as model substances. After single i.v. administration of 98 micromoles of the pure enantiomers per kg b.wt., concentrations were measured by gas-liquid chromatography. The l-form exhibited a longer plasma half-life (23.3 +/- S.E. 1.0 hour) than the d-form (16.3 +/- 1.0 hour, P less than .005). Volumes of distribution and renal clearances were practically identical. The differences in plasma half-lives of PEH were explained by stereoselectivity of hepatic hydroxylation: an approximately 10-fold differences was found in urinary excretion of their major metabolities, d- and l-hydroxyphenylethylhydantoin (HPEH). Furthermore, in bile 7.3 +/- 1.6 mumol of of d-HPEH were eliminated within the first 6 hours, whereas l-HPEH could not be detected. The preference in biliary output of d- compared with l-PEH is consistent with the idea that both hepatic uptake and microsomal hydroxylation of PEH contribute to the high degree of stereoselectivity. In view of similar extrahepatic, but different metabolic behavior of these enantiomers, they represent an interesting research tool for in vivo studies of drug metabolism: in otherwise identical conditions, two different rates of PEH hydroxylation may be studied.

Animals↗

PubMed1976

Aminopyrine demethylation measured by breath analysis in cirrhosis.

The method of measuring the rate of aminopyrine demethylation by breath analysis was assessed in 23 normal subjects and 20 patients with cirrhosis. Carbon 14 aminopyrine specifically labeled at the two N-methyl groups was administered by mouth in a dose of 9 mg/kg, including a total radioactivity of 2 muCi. The decay of the specific activity of 14CO2 in breath (kb) was found to correlate (r = 0.91) with the disappearance of aminopyrine from plasma (KP). In normal volunteers, kb was 22.4%/hr; in patients with alcoholic and nonalcoholic cirrhosis it was depressed to 8.4%/hr (p less than 0.001). The degree of functional impairment found with the breath test was similar to the sulfobromophthalein (BSP) disappearance curve and the galactose elimination capacity. Although many questions relating to the aminopyrine breath test remain open, our data confirm and extend previous studies of 14CO2 breath analysis after 14C-aminopyrine administration. It is concluded that it represents a simple and noninvasive procedure which quantitatively reflects the microsomal function of the cirrhotic liver.

Adult↗

PubMedDate not supplied

Pharmacokinetics of R-enantiomeric normephenytoin during chronic administration in epileptic patients.

Stereoselective metabolism has been demonstrated for mephenytoin (MHT), R-MHT being demethylated to the pharmacologically active metabolite 5-phenyl-5-ethylhydantoin (PEH; nirvanol), and S-MHT undergoing aromatic hydroxylation to 4-OH-MHT, with formation of an intermediate arene oxide metabolite. PEH is responsible for the therapeutic effect, whereas 4-OH-MHT is rapidly eliminated by the kidneys. The arene oxide metabolite may have implications in MHT toxicity. The metabolism of PEH is also stereospecific. In the present study, the R-enantiomer of PEH (R-PEH; R-normephenytoin) was administered chronically during 8 weeks to four epileptic patients, as a single dose every 3 days. The half-lives of R-PEH ranged from 77.7 to 175.8 h, and correlated closely with the creatinine clearance. Mean urinary recovery of R-PEH was 86.6% of the dose at steady state, with 4-OH-PEH accounting for only 5%. This indicates that, unlike Nirvanol (a racemic mixture of R- and S-PEH), R-PEH is only minimally metabolized, even after several weeks of treatment and despite potential enzymatic autoinduction and heteroinduction by other antiepileptic drugs. Complete blood counts and liver function tests revealed no alteration, and no other adverse effects were noted. If arene oxide intermediate metabolites are indeed involved in the toxicity of MHT and nirvanol, R-PEH may represent a safer alternative.

Adult↗

PubMedDate not supplied

A major pathway of mephenytoin metabolism in man. Aromatic hydroxylation to p-hydroxymephenytoin.

A major metabolite of the antiepileptic drug mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) has been identified in urine after a single oral dose of 100 mg of mephenytoin in man. Using chemical synthesis, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy, we established its chemical structure as 3-methyl-5-ethyl-5-(4-hydroxyphenyl)hydantoin (4-OH-M) which is a product of aromatic hydroxylation of mephenytoin in man. Quantitative determinations of 4-OH-M in urine of 10 volunteers showed that 43 +/- 7% (SD) of a single oral dose of 100 mg of mephenytoin were eliminated as the glucuronide of this metabolite. Urinary elimination of the demethylated metabolite, 5-ethyl-5-phenylhydantoin (Nirvanol), was low (1% of the dose per 24 hr) emphasizing the importance of 4-OH-M as the major metabolite after a single oral dose of mephenytoin. Other products of mephenytoin hydroxylation (2-OH-M, E-OH-M, or aliphatically hydroxylated 2-OH-ethyl-M) were not detectable under the conditions selected (less than 1 mumol/24 hr).

Adult↗

PubMedDate not supplied

Identification of mephenytoin metabolites in the dog.

In two dogs p-hydroxymephenytoin, m-hydroxymephenytoin, 5-ethyl-5-phenylhydantoin (nirvanol), and 5-ethyl-5-(p-hydroxyphenyl)hydantoin (p-hydroxynirvanol) were identified by use of synthetic metabolites as standards for comparison.

Animals↗

PubMedDate not supplied

Induction of drug-metabolizing enzymes by the enantiomers of normephenytoin in the rat.

The influence of the S- and R-enantiomers of normephenytoin on various hepatic drug-metabolizing enzyme systems has been investigated in the rat. Both enantiomers proved to be potent enzyme inducers. In vivo, 14C-aminopyrine breath test half-life was decreased and 24-hr urine recovery of 14C after 14C-diphenylhydantoin administration was increased. In vitro, hepatic cytochrome P-450 concentration was increased and there were increases in activity of oxidative metabolism of aminopyrine, aniline, hexobarbital, and p-nitroanisole, and in activities of glucuronyltransferase and glutathionetransferase enzymes. There were differences in the disposition of R- and S-enantiomers indicating that (S)-normephenytoin was eliminated more rapidly. Taking this into consideration, the two enantiomers were equipotent enzyme-inducing agents.

Animals↗