J. P. Kampmann

Disposition of Antipyrine and Phenytoin Correlated with Age and Liver Volume in Man

SummaryThe half-life and metabolic clearance rale (MCR) of antipyrine and phenytoin were determined in 14 young [mean age: 28.8 ± 8.3 (SD) years] and in 14 elderly [mean age: 83.5 ±7.1 (SD) years] subjects and correlated with liver volume, which was determined by ultrasonic scanning, to see if an age-dependent difference in drug metabolism could be explained by a reduced liver weight with age.The size of the liver was smaller in the elderly subjects even when related to decreased body surface. A significant decrease in serum albumin in the elderly compared with the younger group was also noted. The half-life of antipyrine was significantly longer in the elderly than in the younger group, 756 ± 318 and 465 ± 110 minutes, respectively, and the MCR was correspondingly lower in the elderly even when calculated per litre of liver volume, 22.8 ± 7.8 and 36.3 ± 8.9ml/minute/L liver volume, respectively. No significant differences in the 2 age groups were found in half-life and total clearance of phenytoin, but a reduced free phenytoin clearance was demonstrated in the elderly (240 ± 92ml/minute/L liver volume) compared with the younger (325 ± 81 ml/minute/L liver volume) group. No significant correlation was found between liver volume and the half-life of antipyrine and phenytoin. However, a significant correlation was demonstrated between liver volume and MCR of antipyrine as well as between total and free clearance of phenytoin. No correlation was found between the half-lives of the 2 drugs, while a significant correlation existed between the clearance values.It is suggested that the age-dependent reduction in drug clearance is due not only to a smaller liver volume, but is also a result of a reduced capacity of the liver microsomes per unit of liver in the elderly. With regard to age-dependent changes in drug metabolism, the protein binding of the actual drug has to be taken into consideration.

Excretion of methimazole in human milk

SummaryIt is universally stated that antithyroid drugs are concentrated in human milk and are thus contraindicated during breast-feeding. We recently showed, however, that propylthiouracil (PTU) was not concentrated in milk and a study has now been made of the excretion of another widely used antithyroid drug carbimazole (CMI) in human milk. Methimazole (MMI) in blood and milk from five lactating women was measured after oral administration of CMI 40 mg, which is rapidly and completely transformed to the active antithyroid compound MMI. One hour after CMI, the mean serum-MMI reached 253 µg/l and the mean concentration of MMI in milk reached 182 µg/l. MMI was found to be unionized and not to be protein bound in serum, and it occured in milk in the same concentration as in serum; the mean milk/serum ratio was 0.98. The mean total amount of MMI excreted in milk over 8 h was 34 µg (SEM ± 5,n=5), i.e. 0.14% of the dose administered.

L-thyroxine treatment of diffuse non-toxic goitre evaluated by ultrasonic determination of thyroid volume.

The effect of a daily dose of 150 μg 1‐thyroxine for one year was studied in forty‐five patients with diffuse non‐toxic goitre. Thyroid volume was evaluated by ultrasonic scanning. A decrease in the median value of the thyroid volume of about 20% was found after 3 months of therapy and no further change in the median value was observed in the following 9 months of treatment. About 50% of the patients showed a response to therapy and about 30% obtained normal size of the thyroid gland. Median value of the thyroid volume returned to pretreatment value 3 months after thyroxine therapy was stopped.

Renal excretion of drugs

An age-dependent decrease in renal function seems to be one of the most important physiological factors responsible for altered pharmacokinetics in the elderly—a subject recently reviewed elsewhere (Triggs and Nation, 1975; Crooks, O’Malley and Stevenson, 1976).

A HPLC method for the simultaneous determination of disopyramide, lidocaine and their monodealkylated metabolites

This paper describes a simple high-performance liquid chromatographic method for the determination of disopyramide and lidocaine simultaneously with their dealkylated metabolites. After basic tert-butyl methyl ether extraction and back-extraction with phosphoric acid, the drugs and their metabolites were injected into a Supelcosil CN column and the absorbance of the eluate was measured at 215 nm. The sensitivity was 0.3 mumol/l and the obtained precision, selectivity and stability during storage were adequate for the performed clinical studies in patients therapeutically treated with disopyramide and/or lidocaine. Some results from the clinical studies are briefly presented.

Kinetics of disopyramide in decreased hepatic function

The elimination kinetics of disopyramide was studied in 9 patients with decreased hepatic function (DHF) due to histologically verified cirrhosis of the liver, and in 11 patients with ischaemic heart disease (IHD). Disopyramide 100 and 150 mg was given intravenously as a bolus to the patients with IHD and DHF, respectively, followed by a continuous infusion of disopyramide 0.3 (DHF group) and 0.4 mg · min−1 (IHD group) until steady-state was achieved. A significant (p<0.001) positive correlation between the percentage unbound and total serum concentration of disopyramide was demonstrated in both groups. The percentage of unbound disopyramide at a total serum concentration of 5.9 µmol·l−1 was 45.5% and 19.4% in the DHF and IHD groups, respectively. A negative correlation (r=−0,751,p<0.05, and r=−0.827,p<0.01 in the IHD and DHF patients, respectively) between the free fraction of disopyramide and alpha1-acid glycoprotein was observed. The serum concentration of alpha1-acid glycoprotein, the major binding protein of disopyramide, was significantly lower in the patients with DHF. The clearance of unbound disopyramide and its total volume of distribution and half-life were significantly lower in the DHF patients. No difference in total elimination clearance could be demonstrated. The clinical implication of the present findings appear to be that the dosage of disopyramide should be reduced by 25% when it is given intravenously to patients with decreased hepatic function.

Pharmacokinetics of Various Preparations of Organic Nitrates

SummaryThe pharmacokinetics of different formulations of glyceryl trinitrate, isosorbide dinitrate, isosorbide 5-mononitrate and isosorbide 2-mononitrate are reviewed.

Atenolol inhibits the elimination of disopyramide

SummaryThe effect of atenolol on the total elimination of disopyramide and its main dealkylated metabolite was studied in 6 patients and 3 volunteers. During administration of 50 mg atenolol b.i.d. the clearance of disopyramide decreased significantly (p<0.02) from 1.90±0.71 (X±SD) to 1.59±0.68 ml/kg/min, while its half-life, concentration of the metabolite, and the volume of distribution remained unchanged. The reduction in the clearance of disopyramide by atenolol might contribute to the alleged pharmacodynamic interaction between disopyramide and β-blocking drugs.

Haemodynamic Effects and Kinetics of Concomitant Intravenous Disopyramide and Atenolol in Patients with Ischaemic Heart Disease

SummaryThe haemodynamic effects of concomitant intravenous administration of disopyramide (Norpace) and atenolol (Tenormin) were studied in a cross-over trial in 7 patients with ischaemic heart disease. Following 150 mg disopyramide i.v. the cardiac index (CI) and stroke volume index (SVI) decreased by 14% and 26%, respectively and the heart rate (HR) and preejection period index (PEPI) increased by 13% and 19%, respectively. A decrease in CI of 14% and HR of 21%, respectively were noted after intravenous administration of 7.5 mg atenolol; PEPI increased by 10% whereas SVI remained unchanged. The cardiac Index (CI) fell by 33% following the administration of both drugs. The effect on CI of the two drugs was additive. The effect of disopyramide and atenolol on HR, SVI and PEPI was not significantly modified by coadministration of the other drug. No change in blood pressure was observed after disopyramide or atenolol. A correlation (ρ) of 0.540 and 0.387 was observed between the change in PEPI and the log free and total serum concentrations of disopyramide, respectively. Combined intravenous use of the two drugs in patients with incipient or overt heart failure is not recommended, unless it is due to the arrhythmia to be treated.