Gunnar Alván

A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquin

Debrisoquin hydroxylation capacity determined as the ratio of debrisoquin to 4‐OH‐debrisoquin (DMR) in urine after a single oral dose (10 mg) was studied in 52 nuclear families comprising 226 subjects. The relative importance of genetic and environmental factors for DMR was studied by path analysis. There was a significant negative correlation between DMR and coffee intake but no significant correlations between DMR and sex, age, alcohol intake, or smoking habits. Path analysis showed that genetic heritability was 0.79 while cultural heritability was only 0.06. Complex segregation analysis gave evidence for a major locus with incomplete dominance (d = 0.28) between a recessive and an additive gene. The frequency of the major gene was 0.31, allowing an estimate of the frequency of slow hydroxylators in the Swedish population of 9.4%. There was also evidence for a multifactorial component accounting for 14% of the total variation. It was not possible to distinguish between the different genotypes within the rapid hydroxylator phenotype. Our data agree with previous studies in British and German populations showing that two alleles at a major autosomal locus can explain most of the observed variation in DMR. The frequency of slow hydroxylators in Sweden is very similar to that reported in other European studies. The debrisoquin metabolic phenotype seems to be extensively controlled by a monogenic system and not significantly influenced by environmental factors or age.

Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of tolterodine

To determine whether cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamics (heart rate, accommodation, and salivation) of tolterodine and its 5‐hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin (INN, debrisoquine).

Pharmacokinetics of fluoride in man after single and multiple oral doses

SummaryThe doses of fluoride (F) recommended in the literature for caries prevention and for the treatment of osteoporosis vary. This partly reflects inadequate knowledge of F pharmacokinetics. In the present study various single and multiple oral doses of F were given to eight volunteers, who had a strictly controlled F intake in the diet. The resulting plasma and parotid saliva concentrations as well as urinary output of F were measured. The plasma data fitted a two-compartment open model with a β-slope half-life ranging between 2 and 9 h. Plasma clearance was 0.15±0.02 (SD) liter/kg/h. Data from the highest dose (10 mg) were fitted to both two- and three-compartment models, and there was no significant difference between them. Multiple doses of F 3.0 or 4.5 mg yielded steady state concentrations ranging from 54 to 145 ng/ml. About 50 per cent of the given dose was recovered in the urine, which is indicative of considerable accumulation in the body. The saliva F/plasma F concentration ratio was 0.64 with a coefficient of variation of 5%.

Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration

Physiologic indirect‐response models have been proposed to account for the pharmacodynamics of drugs with an indirect mechanism of action, such as furosemide. However, they have not been applied to tolerance development. The aim of this study was to investigate the development of tolerance after multiple intravenous dosing of furosemide in healthy volunteers.

Nonlinear assessment of phenytoin bioavailability

The bioavailability of phenytoin, a drug subject to capacity-limited disposition, was examined using linear and nonlinear pharmacokinetic techniques. The linear method (comparative areas) underestimates the essentially complete bioavailability of this drug from capsules (Epanutin, Parke-Davis). The error incurred in using area ratios is inversely related to the rate of absorption of the drug. The time course of absorption of phenytoin capsules is irregular and prolonged over nearly 2 days.

Mechanism of Absorption Enhancement in Humans After Rectal Administration of Ampicillin in Suppositories Containing Sodium Caprate

AbstractPurpose. The medium chain fatty acid sodium caprate (C10) is approved as an absorption enhancer but its mechanism of action has not been studied in humans. The aim of this study was to investigate the mechanism of action of C10 in human subjects after rectal administration. Methods. Twelve healthy human subjects were randomised to receive ampicillin suppositories with (AM-C10) or without (AM) C10. Serum and urine samples were collected and analysed for ampicillin by HPLC. Rectal biopsies were taken before and 25 min (approximate time of maximum serum concentration, Cmax, for ampicillin) and 185 min (during the final part of the elimination phase) after rectal administration of the suppositories. The osmolality of the rectal fluid was also measured. Results. AM-C10 administration increased Cmax, area under the serum concentration-time curve (AUC) and urinary recovery of ampicillin 2.6-, 2.3- and 1.8-fold, respectively, compared to AM. Histological examination of the biopsies showed that AM-C10 exposure resulted in reversible mucosal damage that occurred at the same time as the Cmax for ampicillin while AM prolonged mucosal damage. A reversible increase in rectal fluid osmolality was observed with both treatments. Conclusions. AM-ClO-enhanced absorption of ampicillin coincides with non-specific damage to the rectal mucosa. C10 itself as well as the suppository base and the hyperosmolality of the rectal fluid contributed to this effect. However, the histological damage was reversible with AM-C10, suggesting that C10 also has a protective effect on the rectal mucosa.

Drugs during pregnancy: an issue of risk classification and information to prescribers.

SummaryThe Swedish system for the classification of fetal risk of drugs was the first of its kind and was implemented in 1978. Drugs for use in pregnant women are classified in 4 general categories — A to D. The US Food and Drug Administration (FDA) introduced a system in 1979 also using the letters A to D, together with an X category. However, the definitions differ considerably between the FDA system and the Swedish system, resulting in a very different allocation of drugs to the respective categories.In the Swedish system, category A includes drugs that have been extensively used and/or for which there are reliable clinical data indicating no evidence of disturbance of the reproductive process. Category B includes drugs for which data from pregnant women are insufficient for making any solid estimation of human teratogenic risk, and classification is therefore based on animal data, with allocation to 3 subgroups. For products in category C, the pharmacological action of the drug may have undesirable effects on the human fetus or newborn infant. Finally, category D contains drugs for which human data indicate an increased incidence of malformations. The categorisation statement is always followed by a short explanatory text. In contrast to the FDA system, the Swedish system has been well accepted, as judged by an interview study including 934 physicians and pharmacists. We believe that much of the American dissatisfaction may be a consequence of shortcomings in the category definitions of the FDA system. The FDA system requires an unrealistically high quality of data, e.g. the availability of controlled studies in pregnant women that fail to demonstrate a risk to the fetus are needed for a drug to be assigned to category A. Consequently, the majority of drugs on the US market are allocated to category C, interpreted as ‘risk cannot be ruled out’. The distribution of drugs into the various categories is thus very different between the Swedish and FDA systems.We think that the issue of this debate reflects a fundamental problem related to public health information: how should a large, compounded, changing and difficult to evaluate databank be organised before it is made available to professionals and secondarily to lay people?

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.

Nonlinearity of amoxicillin absorption kinetics in human

SummarySpecialised gastrointestinal absorption of amoxicillin has been suggested in man and has been demonstrated in animals. In order to study the rate and extent of amoxicillin absorption, six healthy subjects were given 500 mg IV and two oral doses (500 mg and 3 g as a suspension). Absorption kinetics was analysed by compartmental modelling, noncompartmental methods and by calculation of absorption rates using deconvolution.Dose-dependency of the extent of amoxicillin absorption was observed, with a lower than expected mean maximum plasma concentration (49%), and fraction of the dose absorbed (39%) after the 3 g dose calculated from the 500 mg dose, assuming kinetic linearity. Zero-order kinetics of absorption was apparent in some subjects after the 500 mg dose, both from model fitting and absorption rate profile. However, no pattern consistent with pure first-order or zero-order absorption was observed after both oral doses in any individual. The dose-dependency of amoxicillin absorption was confirmed by a trend to an increased time of absorption for the high dose.The results show the variable nature and nonlinearity of the gastrointestinal absorption of amoxicillin and indicate the involvement of a number of factors, in addition to simple diffusion.

Determination of chloroquine and its desethyl metabolite in whole blood: an application for samples collected in capillary tubes and dried on filter paper

A high performance liquid chromatography method for analysis of chloroquine and desethylchloroquine was adapted for 75 microliters aliquots of whole blood obtained by finger-prick and dried on filter paper. The precision of the method was satisfactory at whole blood concentrations of 40 nmol/L (coefficient of variation, 5%). The dried samples were stable for at least 7 weeks at 20 degrees C. The concentrations in venous whole blood and in dried samples correlated well. The correlation coefficient was 0.99 for chloroquine and 0.97 for desethylchloroquine. Chloroquine concentrations were marginally but significantly higher in venous whole blood. When fitted to a linear equation (y = bx + a) the relationship was y = 0.96x + 0.03. Desethylchloroquine concentrations did not differ significantly in venous whole blood and in finger-prick blood dried on filter paper. The method is specific and sensitive enough for pharmacokinetic studies and can be used in areas with limited technical facilities.