Margareta Lind

Effect of pentobarbital on the disposition of alprenolol.

Alprenolol was administered orally and intravenously to 5 healthy subjects before and after IO to 14 daily doses of 0.1 gm pentobarbital. The area under the plasma concentration time curve after an oral 200‐mg dose decreased from 706 ± 277 to 154 ± 48 ng/ml . hr (mean and SD) with the barbiturate treatment, but there was no significant change in elimination rate. The change in area corresponded to an increase in extraction by the liver from 0.72 ± 0.13 to 0.93 ± 0.01. The disposition ofa 5.0‐mg intravenous dose of alprenolol did not change significantly after pentobarbital treatment. There was no indication of a marked change in hepatic blood flow estimated from the clearance of alprenolol after intravenous administration. It is concluded that pentobarbital administration induces the metabolism ()f alprenolol in man and that the pharmacokinetic theories derived for hepatic extraction of drugs subject to a high metabolic clearance can be successfully applied.

First pass hydroxylation of nortriptyline: Concentrations of parent drug and major metabolites in plasma

SummaryNortriptyline was given orally and intramuscularly to six depressed patients. Plasma concentrations of parent drug and the unconjugated and conjugated principal metabolite, 10-hydroxynortriptyline, were determined by mass fragmentography. There was a significant decrease in the area under the nortriptyline plasma concentration — time curve after the oral route of administration, whilst the elimination rate was unchanged. With the oral dose, plasma concentrations of the metabolites were higher and peaked earlier than after intramuscular administration, whilst the opposite was true for the parent compound. This proves that the difference in bioavailability between the two routes of administration was due to first pass metabolism. As determined from the ratio between corresponding areas, the relative bioavailability of the oral dose was 66±21 S.D. per cent. This fraction is higher than that reported previously when intravenous nortriptyline was used as the reference dosage form.

Plasma disappearance of nortriptyline in a newborn infant following placental transfer from an intoxicated mother: Evidence for drug metabolism*

The plasma disappearance of nortriptyline in a mother and her newborn child was studied after the pregnant woman took an overdose of nortriptyline one day before delivery. The identity of nortriptyline and its main metabolite, 10-hydroxynortriptyline, in the infants plasma was ascertained with mass fragmentography. The peak concentration of nortriptyline in the infants plasma corresponded to less than 20 per cent of that in the mother. The plasma half-lives of notriptyline in the mother and child were 17 and 56 hours, respectively. High concentrations of 10-hydroxynortriptyline were found in the infants urine during the first and fourth days after birth. It is concluded that nortriptyline is readily transferred through the human placental barrier and that it can be metabolized by the infant.

On the question of dose-dependent chloroquine elimination of a single oral dose

Subjects (n = 45) were randomly given single oral doses of 2 (n = 11), 3 (n = 9), 5 (n = 8), 10 (n = 10), or 15 mg/kg (n = 7) chloroquine base. Chloroquine was analyzed by HPLC in serum samples taken at 3 to 168 hr after dosing. AUCs, calculated for the time period of 0 to 168 hr were proportional to the doses. Mean AUC value increased 6.7 times when the dose was increased 7.5 times (from 2 to 15 mg/kg). These data do not support the existence of significant capacity‐limited chloroquine elimination within the dose range studied.

Steady-state plasma concentrations of alprenolol in man

SummaryPlasma concentrations of alprenolol during one inter-dose interval and steady-state plasma concentrations have been determined in 30 patients treated for a prolonged period. The latter varied 25-fold between patients who received identical doses. Peak plasma concentrations were achieved at similar times in different patients, but only the level 5–7 h after administration was well correlated (r=0.997) with the steady-state concentration. The type of pharmacokinetic analysis described here is recommended for studies of the relationships between plasma concentration and effects of drugs with short half-lives.

Importance of “first-pass elimination” for interindividual differences in steady-state concentrations of the adrenergicβ-receptor antagonist alprenolol

Seven healthy volunteers showing a fourteenfold range in steady-state plasma concentrations on oral alprenolol (200 mg b.i.d.) were investigated by administration of 5 mg of the drug intravenously and then 50, 100, 150, and 200 mg as single oral doses. The rank order for individual steady-state plasma concentrations was the same as that for the relative bioavailability of the 200 mg dose. The area under the plasma concentration-time curve showed a nonlinear increase with the dose. As the relative availability was a good predictor of steady state while clearance after intravenous administration was not, it was concluded that differences in first-pass elimination markedly contribute to the interindividual variability in steady state plasma concentrations. After pentobarbital treatment, the area under the plasma concentration curve of the 200 mg dose was decreased to 32% and 59% of the pretreatment values in two subjects, but there was no change in the plasma half-life of alprenolol. This indicates induction of the first-pass extraction of alprenolol in man.

Increased nonrenal clearance and increased diuretic efficiency of furosemide in cystic fibrosis

The pharmacokinetics of furosemide and its diuretic effect were studied in six patients with cystic fibrosis (CF) and in six age‐matched healthy volunteers. Furosemide was given intravenously at a dose of approximately 0.5 mg/kg. Renal excretion of furosemide was decreased in CF because nonrenal clearance was more than twice as high as in controls (p = 0.03). Nonrenal clearance correlated with the volume of distribution (r2 = 0.52, p = 0.01), which makes a difference in the distribution and binding determinants for clearance. Another reason for increased nonrenal clearance could be induction of drug metabolism in CF, but the excretion of furosemide conjugate did not differ significantly between the groups. Although 26% less furosemide was excreted in CF than in controls (p = 0.03), the diuretic response (calculated as excretion of water and electrolytes) did not differ. Thus the diuretic efficiency was higher in CF for Na+ (p = 0.02), Cl− (p = 0.01), K+ (p = 0.07), and volume (p = 0.005). This difference is probably secondary to the different rates of delivery of furosemide into urine.

Induction of theophylline metabolism by pentobarbital.

Theophylline concentrations in plasma and urine were determined during maintenance treatment in nine healthy volunteers during one dosage interval before and after 10 days of simultaneous treatment with pentobarbital (100 mg each night). During the pentobarbital period, total plasma clearance of theophylline increased by 40% (range -4-79%), whereas renal clearance remained unchanged. It is concluded that therapeutic doses of pentobarbital induce the metabolism of theophylline with marked interindividual variation.

Active metabolites of antidepressants: novel aspects of hydroxylation and demethylation in man

The tricyclic antidepressant (TCA) tertiary amines imipramine (IMI) and amitriptyline (AMI) were found, soon after their introduction as drugs, to have active demethyl metabolites—desipramine (DMI) and nortriptyline (NT) (figure 1). These two secondary amines were later introduced as antidepressant drugs. Similarly the potent serotonin (5-HT) uptake inhibitor chlorimipramine (CI) is demethylated to an active secondary amine. In almost every patient the steady state plasma levels of demethylchlorimi-pramine (DMCI) exceeded those of the parent drug (Traskman et al., 1979; Thoren et al., 1980). As the demethyl metabolite is a potent inhibitor of norepinephrine (NE) uptake, demethylation changes the pharmacodynamic profile of the drug (Traskman et al., 1979; Thoren et al., 1980).