Motor unit counting and the caffeine contracture test in malignant hyperthermia.
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Biomedical subjects
Publications and source records attributed to W Kalow.
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Some aspects of the fate of amobarbital were investigated since this drug is being used as a probe to gauge drug oxidation in man. The mean ratio of orally available over intravenously injected amobarbital was established as 0.99 +/- 0.11 (SD), by comparing integrated concentration-time curves, indicating complete absorption and absence of a first-pass effect. One subject ingested 200 mg of amobarbital sodium, and amobarbital concentrations in serum were monitored for 5 days thereafter. Elimination of amobarbital under these conditions followed first-order kinetics. One subject ingested amobarbital 7 times over a period of 3 yr; plasma clearances (32.1 +/- 1.8 [SD]ml/min) exhibited remarkable constancy, while biologic half-lives (26.5 +/- 3.1 hr) and distribution volumes (73.6 +/- 8.0 L) showed some fluctuation. The distribution of parameters of amobarbital elimination was investigated in 36 unrelated subjects. Amobarbital half-lives (23.8 +/- 6.7 hr) appeared to be normally distributed, while the clearances (36.7 +/- 10.0 ml/min) might not follow a normal distribution.
Following the intravenous administration of 125 mg amobarbital sodium in 7 pairs of dizygotic and 7 pairs of monozygotic twins, the time-course of plasma concentrations was observed. The number of detectable compartments varied from subject to subject but was consistently 1 or 2 or 3 within a given individual. The terminal slope of the semilogarithmic concentration-time plot (corresponding to biologic half-life of 22.8 hr) did not represent the elimination rate constant even in persons with apparently single-compartmental characteristics. The redistribution of amobarbital was rapid in comparison with its elimination. The rate of the latter (characterized by kel = 0.051 hr-1, plasma clearance = 37.7 ml/min) could be closely identified with the rate of metabolism. The twin data showed that genetic control was exerted on kinetic parameters characterizing the rate of amobarbital elimination and, therfore, the rate of its metabolism. Correlation analysis suggested that this control was independent of size factors, which were themselves substantially heritable. The genetic analysis of twin data included, in addition to intracelass correlations and Holzinger's H factors, newly developed lower (and upper) bounds of the broad-sense heritability. In pharmacogenetic studies, assessment of model-independent kinetic parameters, such as plasma clearance with or without adjustment for body weight, is recommended.
The adenosine triphosphate (ATP depletion ratio, which is the ratio [ATP] in skeletal muscle equilibrated with carbogen and 4% halothane for 30 minutes divided by [ATP] in skeletal muscle equilibrated with carbogen alone for 30 minutes is less than normal in most but not in all rigid MHS patients. The ratio is normal in non-rigid MHS patients. This diagnostic tool is, therefore, useful in the diagnosis of rigid MH. It is not, however, such a sensitive diagnostic parameter as the caffeine contracture test.
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The concentration of 5,5-diphenylhydantoin (DPH) in serum was determined at selected time intervals in seven healthy male volunteers starting 10 h after an oral dose of 400 mg sodium DPH was given. The data were analyzed according to a one-compartment model assuming first-order kinetics. The mean serum half-life was 19.28 h +/- 5.87 (SD). A positive correlation coefficient (r=0.84, p less than 0.05) was found between the serum DPH half-life and the serum amobarbital half-life in the seven subjects. The urinary levels of free plus conjugated 5-(p-hydroxyphenyl)-5-phenyl-hydantoin were determined for 12 h periods over a minimum of two days following the 400 mg oral dose of sodium DPH. Subjects with a short DPH half-life tended to excrete in urine a greater amount of p-HPPH as compared to subjects with a long DPH half-life. In the case of one subject, the urinary excretion of p-HPPH plateaued five days after DPH administration and the apparent elimination half-life determined from the p-HPPH urinary excretion data was 19.16 h as compared to the value of 19.53 h calculated from the DPH serum levels.
The concentrations of amobarbital in saliva and serum were determined in 5 normal adults following ingestion of 120 mg of sodium amobarbital. There was excellent linear relationship between amobarbital concentrations in saliva and serum (r = 0.993); salivary levels were 36.1% of serum levels. Since the pH of saliva was generally lower than that of blood in man, the degree of ionization of amobarbital in serum and saliva had to be taken into consideration. Estimation of the protein binding of amobarbital in serum from concentrations of amobarbital in saliva and serum was in good agreement with the in vitro data of equilibrium dialysis.
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The presence of ordered phospholipid lamellar structure in inner membranes of mitochondria was detected with the use of a spin-labeled 2,4-dinitrophenol. A phospholipid bilayer may be an important structural and functional component of the inner mitochondrial membrane.
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