C. von Bahr

Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin.

AbstractObjective: The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU) – a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum MT levels differently, inasmuch as the ways they inhibit cytochrome P450 (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation was to test this hypothesis. Methods: Seven healthy subjects participated in three different experiments, which were performed in random order 6–8 days apart. In experiment A, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC0–20) were compared in the three experiments, and differences were statistically evaluated. Results: FLU augmented the MT-AUC0–20 by a factor of 2.8 compared with the effect of placebo (P < 0.01), whereas CIT was without significant effect. More MT was excreted in the urine after ingestion of FLU than after placebo. In contrast, CIT did not influence the MT excretion. A clear relationship was found between serum levels of MT and plasma concentrations of FLU. Conclusion: The serum MT level increased markedly after ingestion of FLU but not after CIT. The exact mechanism behind this finding is unknown, but decreased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is probable. Although exogenous MT, causing high MT concentration in plasma, has sleep-promoting properties in man, it is at this stage unknown whether serum MT concentrations in the range found in this study have similar effects. This has to be given further attention in additional studies.

A comparative study of drug metabolism in the isolated perfused liver and in vivo in rats.

Abstract The plasma half-lives of five drugs, phenylbutazone, antipyrine, oxotremorine, nortriptyline and desmethylimipramine were compared in vivo and in the isolated perfused rat liver. All drugs showed first order elimination in the perfusion experiments over wide concentration ranges. The half-lives in vivo and in the isolated perfused liver agreed well for drugs with a small volume of distribution (antipyrine, oxotremorine and phenylbutazone) but were markedly different for those with a large volume of distribution (nortriptyline and desmethylimipramine). The half lives of the latter two drugs were 30 times longer in vivo than in the perfused liver. After phenobarbital treatment of rats in vivo the elimination rate of phenylbutazone increased both in vivo and in the isolated perfused liver in a parallel manner. The disappearance of this drug was also shown to be associated with the appearance of its metabolite oxyphenbutazone.

Clinical value of assessing prednisolone pharmacokinetics before and after renal transplantation

SummaryThe value of assessing the kinetics of prednisolone for predicting graft survival and the occurrence of adverse effects of long-term treatment with prednisolone was evaluated in 35 renal transplant patients. The subjects were given an oral test dose of 30 mg prednisolone before, shortly after and 3 months after transplantation. Serum samples were assayed for prednisolone and endogenous hydrocortisone by a specific HPLC method. Intrinsic prednisolone clearance differed less than three-fold (range 0.10–0.27 l/kg·h) between the patients and was relatively stable at different times in each of them. From the data obtained it was not possible to predict rejection episodes. If rejection occurred, however, a high clearance (≥0.20 l/kg·h) appeared to be deleterious for the outcome (p<0.05). Patients with Cushingoid habitus did not differ from non-Cushingoid patients with respect to prednisolone clearance or endogenous hydrocortisone level. 7 out of 8 cases of steroid-related complications (steroid diabetes, psychosis, duodenal ulcer, perforation of the colon and osteonecrosis) occurred in patients with a clearance lower than 0.16 l/kg·h (ns). The one-year graft survival rate was 67% in patients with a clearance ≥0.16 l/kg·h, compared to 85% in patients with a lower clearance (ns). Although some correlation may exist between prednisolone kinetics, graft survival and steroid-related complications (not statistically significant in the present study), the predictive value of prednisolone kinetics is probably small in routine clinical work.

Kinetics of Nortriptyline (NT) in Rats in vivo and in the Isolated Perfused Liver: Demonstration of a ‘First Pass Disappearance’ of NT in the Liver

We have studied the time course of the concentrations of nortriptyline (NT) in whole rat blood in vivo after intravenous, intraperitoneal and oral administration and the hepatic upt

Does hepatic metabolism of melatonin affect the endogenous serum melatonin level in man

Melatonin (MT) is metabolized in the liver by cytochrome P450 (CYP) 1A2 but its importance for the metabolic process has not been fully elucidated. Therefore, the objective of this investigation was to study whether patients with different CYP1A2 activity would have different nocturnal serum MT levels. For that purpose serum MT concentrations were determined every second hour during the night in 12 healthy subjects and their MT areas under the curve (MT-AUCs) were calculated. Caffeine (CA) clearance was determined in advance. It is generally accepted that CA clearance reflects CYP1A2 activity. This made it possible to evaluate whether a relationship prevails between endogenous MTAUCs and CYP1A2 activity. If CYP1A2 is of importance for the metabolism of MT one would expect to find an inverse correlation between the MT-AUCs and the CA clearance. However, such correlation did not exist in the current study (Rs=-0.021, NS). Since endogenous MTAUC is dependent not only on MT elimination by CYP1A2 but also on MT secretion, it is possible that an increased MT secretion counterbalances an increased hepatic MT metabolism. If so, this could explain why the MT-AUCs and the CA clearance values were not inversely correlated in this study.

The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes

SummaryThe chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of β-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (predrug) at 2 h (rs=0.72), 4 h (rs=0.84) and 6 h (rs=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.

Genetic Variability in Man as a Complicating Factor in the Extrapolation of Toxicological Data from Animals

ABSTRACT It is well established that pathways and especially rates of drug metabolism vary not only between but also within species, particularly in humans. This paper discusses the implications of interindividual variability in drug metabolism for the clinical evaluation of drugs. Recent pharmacogenetic research strongly suggests the occurrence of polymorphisms in the oxidation of certain drugs, a few percent in the population being slow oxidizers. The clinical pharmacologist must thus be prepared to encounter slow oxidizers during clinical trials. Preliminary appraisal of the extent of interindividual variability in drug oxidation in man may be obtained from in vitro studies using human tissue from a liver bank containing specimens with vastly different rates of metabolism of various “prototype” drugs. Further information may be obtained by studying the fate of a new drug in a panel of subjects who have been phenotyped with regard to those oxidative pathways that appear to be under monogenic control. An important task for clinical pharmacology is to develop simple tests by which the activity of individual drug metabolic processes can be assessed in man. Equally important is to perform detailed drug metabolic studies in subjects who develop unique adverse drug reactions during phases III and IV of clinical drug evaluation. Increased cooperation between drug epidemiologists and experts in drug metabolism may lead to an early identification of “phenotypes at risk” to develop severe concentration-dependent side effects of various drugs.