Increased sensitivity to diltiazem hypotensive effect in an experimental model of high‐renin hypertension

Objectives The aim of this work was to evaluate the pharmacokinetic–pharmacodynamic properties of diltiazem in an experimental model of high‐renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this model to calcium channel blockers. Methods A ‘shunt’ microdialysis probe was inserted in a carotid artery of anaesthetized ACo and control sham‐operated (SO) rats for simultaneous determination of diltiazem plasma concentrations and their effects on mean arterial pressure and heart rate after the intravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levels and cardiovascular effects was established by fitting the data to a modified E_max model. Key findings Volume of distribution was greater in ACo than in SO rats. Diltiazem plasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO rats after administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo but not in SO rats. No differences were observed in the maximal bradycardic effect comparing both experimental groups, and sensitivity (S₀) to diltiazem chronotropic effect was similar comparing SO and ACo rats. Differences were not found in the maximal response of the hypotensive effect comparing SO and ACo rats, but the S₀ to diltiazem hypotensive effect was greater in ACo rats than in SO rats. Conclusions ACo induced profound changes in diltiazem pharmacokinetic behaviour. In addition, our results suggested an increased sensitivity to diltiazem blood pressure lowering effect in experimental renovascular hypertension with high‐renin levels.     

Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats

Aim:

To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats.

Methods:

Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 μg/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments.

Results:

Exenatide exhibited rapid absorption with k_a=4.45 h^-1, and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated S_m1 of 0.822 and SC₅₀ of 4.02 μg/L. It was demonstrated that insulin stimulated glucose dissipation (S_m2=0.0513) and inhibited the production of glucose (I_m=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed.

Conclusion:

The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.     

THE INFLUENCE OF AGE AND SEX ON CARDIAC,RENAL AND CAUDAL ARTERY CATECHOLAMINE CONTENT IN SPONTANEOUSLY HYPERTENSIVE (SHR) AND WISTAR KYOTO (WKY) RATS

• 1 Noradrenaline (NA), adrenaline (A) and dopamine (DA) levels were measured in the heart, kidney and caudal artery of male and female SHR and WKY rats aged 6, 14 and 28 weeks, and the influence of strain, sex and age on catecholamine content determined.
• 2 Levels of A were elevated in all three regions of SHR compared to WKY rats, independent of age and sex. This may represent increased A accumulation in sympathetic nerves resulting from the increased sympatho-adrenomedullary hyper-reactivity of the SHR strain.
• 3 DA levels were also elevated in the heart and kidney of SHR rats, independent of sex and age.
• 4 NA levels were lower in the heart of SHR rats, but this appeared to be partly a consequence of cardiac hypertrophy and partly due to strain differences between older male but not female rats. Thus a simple association between decreased cardiac NA levels and hypertension appeared unlikely.
• 5 It is emphasised that further genetic studies of F₂ backcross rats would be required to establish an etiological association between these differences in catecholamine levels and differences in blood pressure between the SHR and WKY strains.

     

Antagonistic A2a/D2 receptor interactions in the striatum as a basis for adenosine/dopamine interactions in the central nervous system

From behavioural and biochemical experiments, we have found evidence for the existence of a specific adenosine A_2a receptor/dopamine D₂ receptor interaction in the brain. Behavioural data show that stimulation A_2a receptors inhibits and their blockade potentiates a D₂-mediated locomotor activation in mice and that stimulation of D₂ receptors counteracts on A_2a mediated cataleptic effect in rats. Biochemical data show that, in rat striatal membrane preparations, A_2a receptor stimulation decreases the affinity of D₂ receptors and the transduction of the signal from the D₂ receptor to the G-protein. Based on these findings it is postulated that this A_2a/D₂ interaction might be the main mechanism responsible for the central effects of adenosine agonists and antagonists, like methylxanthines. The increased behavioural effect of methylxanthines after dopamine denervation could be explained by an increased interaction between adenosine A_2a and dopamine D₂ receptors. Membrane preparations-denervated striatum are more sensitive to the effect of adenosine A_2a receptor stimulation. Our results underline the potential antiparkinsonian action of adenosine A_2a antagonists and the potential antipsychotic of adenosine A_2a agonists. © 1993 Wiley-Liss, Inc.     

EFFECT OF EARLY BLOCKADE OF BRADYKININ B2-RECEPTORS ON THE BLOOD PRESSURE PHENOTYPE OF NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS

We evaluated if chronic blockade of bradykinin B₂-receptors by the long-acting antagonist Icatibant (D-Arg,‘Hyp³,Thi⁵,D-Tic⁷,Oic⁸’-bradykinin) affects blood pressure of rats. Pairs of normotensive Wistar Kyoto rats or spontaneously hypertensive rats were mated and their offspring received Icatibant (25 nmol day⁻¹per kg body wt., s.c.) or vehicle from the 2nd day until the 7th week of life. Then, the administration of Icatibant or vehicle was continued by i.p. infusion using Alzet osmotic pumps. At 9 weeks of age, normotensive rats given Icatibant showed greater systolic blood pressure (135±1vs115±1 mmHg in vehicle-treated rats,P<0.01), while heart rate was similar. The group difference regarding blood pressure levels was confirmed by direct intra-arterial measurement. No difference was detected between vehicle- and Icatibant-treated spontaneously hypertensive rats regarding blood pressure increase with aging. In conclusion, chronic blockade of bradykinin receptors by Icatibant alters the adult cardiovascular phenotype of Wistar Kyoto rats, provided that the antagonist is given at the early phases of life. These results suggest that the B₂-receptor is essential for the maintenance of cardiovascular homeostasis during development, whereas it does not exert a protective role against the progression of hypertension in a rat model of genetic hypertension.     

Dose-dependent effect of nutritional sulfite intake on visual evoked potentials and lipid peroxidation

The aim of this study was to clarify the dose-dependent effect of sulfite (SO₃²⁻) ingestion on brain and retina by means of electrophysiological and biochemical parameters. Fifty two male Wistar rats, aged 3 months, were randomized into four experimental groups of 13 rats as follows; control (C), sulfite treated groups (S₁; 10 mg/kg/day, S₂; 100 mg/kg/day, S₃; 260 mg/kg/day). Control rats were administered distilled water, while the other three groups were given sodium metabisulfite (Na₂S₂O₅) of amounts mentioned above, via gavage for a period of 35 days.All components of visual evoked potential (VEP) were prolonged in S₂ and S₃ groups compared with S₁ and C groups. Plasma-S-sulfonate levels, which are an indicator of sulfur dioxide (SO₂) exposure, were increased in Na₂S₂O₅ treated groups in a dose-dependent manner. Furthermore, the significant increments in thiobarbituric acid reactive substances (TBARS) and 4-hydroxy-2-nonenal (4-HNE) levels occurred with increasing intake of Na₂S₂O₅. Though not significant, glutathione (GSH) and oxidized glutathione (GSSG) levels were observed to decrease with increasing doses of Na₂S₂O₅.In conclusion, Na₂S₂O₅ treatment in rats caused a dose-dependent increase in lipid peroxidation and all VEP latencies. The data indicate that lipid peroxidation could play an important role in sulfite toxicity.     

The Absence of Stereoselective P-Glycoprotein-mediated Transport of R/S-Verapamil Across the Rat Jejunum

We have studied the potential stereoselective transport and metabolism of R/S-verapamil in rat jejunum, in-situ. A regional single-pass perfusion of the rat jejunum was performed on 24 rats in six separate groups. The effective permeability (P_eff) was assessed for three different concentrations of verapamil, 4, 40 and 400 mg L^?1. The P_eff of each enantiomer was also determined at 400 mg L^?1 when chlorpromazine (10 mM) was added to the perfusion solution. Two other groups of rats received R/S-verapamil as an intravenous infusion and the intestinal secretion and metabolism were studied by simultaneously perfusing the jejunum with a control or with chlorpromazine (10 mM) added. The concentrations in the outlet perfusate of each enantiomer of verapamil and norverapamil were assayed with HPLC. R/S-Verapamil is a high permeability drug in the proximal rat small intestine throughout the luminal concentration range studied and complete intestinal absorption was expected. There was an increase of P_eff from 0.42 times 10^?4 cm s^?1 to 0.80 times 10^?4 cm s^?1 (P < 0.05) at concentrations from 4 to 400 mg L^?1, respectively. The observed concentration-dependent jejunal P_eff and fraction absorbed (P < 0.05) of R/S-verapamil is consistent with the saturation of an efflux mechanism. When chlorpromazine (a P-glycoprotein inhibitor/substrate) was added the jejunal P_eff increased to 1.47 times 10^?4 cm s^?1. There was no difference between the P_eff of the two enantiomers in any of these experiments. The efflux of R/S-norverapamil into the rat jejunum was high after intravenous administration of R/S-verapamil, suggesting extensive metabolism in the enterocyte. In conclusion, both R/S-verapamil enantiomers are P-glycoprotein substrates, but there is no stereoselective transport of R/S-verapamil in the rat jejunum. The results also suggests that R/S-norverapamil is formed inside the enterocytes.     

Differential activation and inhibition of different forms of rat liver glutathione S-transferase by the herbicides 2,4-dichlorophenoxyacetate (2,4-D) and 2,4,5-trichlorophenoxyacetate (2,4,5-T)

The predominant forms of the dimeric enzyme glutathione S-transferase were purified from rat liver. Forms Y_bY′_b and Y_bY_b (also known as forms C and A, respectively) could be almost completely inhibited by 2,4-dichlorophenoxyacetate (2,4-D). Half-maximal inhibition was obtained at 0.5 mm 2,4-D. Inhibition was seen even at extrapolated infinite concentrations of both substrates for Y_bY_b but not Y_bY′_b. These same forms could also be inhibited 70 to 80% by 2,4,5-trichlorophenoxyacetate (2,4,5-T) with half maximal inhibition occurring at 0.2 mm. Glutathione S-transferase from Y_aY_a was maximally inhibited by 72 and 30%, respectively, by 2,4-D and 2,4,5-T. The 30% inhibition of Y_aY_a caused by 2,4,5-T was shown to reduce the nearly complete inhibition caused by a previously characterized inhibitor, namely bile acids. This suggests competition for a common binding site on the enzyme. In contrast to the above results, it was found that form Y_cY_c (also termed AA) was activated 2.7-fold by 2,4,5-T and 1.4-fold by 2,4-D. This activation could be blocked by chenodeoxycholate which, by itself, did not affect the activity of the enzyme. The effects of 2,4,5-T and 2,4-D on the heterodimer Y_aY_c (also termed form B) were intermediate between their effects on Y_aY_a and Y_cY_c, suggesting that each subunit contributes its unique property to the heterodimer. The microsomal membrane-bound form of glutathione S-transferase was also examined and found to be inhibited by both 2,4-D and 2,4,5-T. However, unlike the inhibitions of soluble forms, 2,4,5-T caused more extensive inhibition than 2,4-D. It is concluded that exposure to 2,4-D and 2,4,5-T can limit the ability of glutathione S-transferase forms Y_bY_b and Y_bY′_b to metabolize electrophilic toxins. This capacity to potentiate the toxicity of certain electrophiles indicates a need to study the effect of herbicides on glutathione S-transferases from human tissues.     

Genetic background of resistance to cadmium-induced testicular toxicity in inbred Wistar-Imamichi rats

We have previously reported that inbred Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced testicular toxicity compared with inbred Fischer 344 (F344) rats. The present study was to elucidate the genetic background of resistance to Cd-induced testicular toxicity in WI rats. The genetic analysis of susceptibility to Cd-induced testicular toxicity was conducted by using Cd-resistant WI and Cd-sensitive F344 strains as the parental rats and by using the testicular hemoglobin level as the indicator. In the frequency distribution of testicular hemoglobin levels in parental, first filial (F₁) and second filial (F₂) rats treated with Cd at a dose of 2.0 mg/kg, F₁ rats had testicular hemoglobin levels intermediate to WI and F344 rats, and F₂ rats segregated into three groups of low, intermediate, and high phenotypes at the expected ratio. Furthermore, the backcross progeny between WI and F₁ or between F344 and F₁ segregated into two groups with the expected ratio. Based on a simple Mendelian genetic analysis, these segregation patterns lead us to conclude that two codominant alleles at a gene locus are responsible for the susceptibility to Cd-induced testicular toxicity in rats. This is the first report for the genetic analysis of susceptibility to Cd-induced testicular toxicity in inbred rat strains.     

Understanding the Differences Between Cocrystal and Salt Aqueous Solubilities

This work challenges the popular notion that pharmaceutical salts are more soluble than cocrystals. There are cocrystals that are more soluble than salt forms of a drug and vice-versa. It all depends on the interplay between the chemistry of both the solid and solution phases. Aqueous solubility, pH_max, and supersaturation index (SA = S_CC/S_D or S_salt/S_D) of cocrystals and salts of a basic drug, lamotrigine (LTG), were determined, and mathematical models that predict the influence of cocrystal/salt K_sp and K_a were derived. K_sp and SA followed the order LTG-nicotinamide cocrystal (18) > LTG-HCl salt (12) > LTG-saccharin salt (5) > LTG-methylparaben cocrystal (1) > LTG-phenobarbital cocrystal (0.2). The values in parenthesis represent SA under nonionizing conditions. Cocrystal/salt solubility and thermodynamic stability are determined by pH and will drastically change with a single unit change in pH. pH_max values ranged from 5.0 (saccharin salt) to 6.4 (methylparaben cocrystal) to 9.0 (phenobarbital cocrystal). Cocrystal/salt pH_max dependence on pK_sp and pK_a shows that cocrystals and salts exhibit different behavior. Solubility and pH_max are as important as supersaturation index in assessing the stability and risks associated with conversions of supersaturating forms.     

REDUCED INHIBITORY ACTIONS OF ADENOSINE A1 AND K1-OPIOID RECEPTOR AGONISTS ON β-ADRENOCEPTORS IN SPONTANEOUSLY HYPERTENSIVE RAT HEART

1. The modulatory actions of both adenosine A₁ and K₁-opioid receptor agonists on β-adrenoceptor stimulation in the heart of both spontaneously hypertensive rats (SHR) and nor-motensive Wistar-Kyoto (WKY) rats were compared. 2. In both types of rats, bot. R(-)-N⁶-(2-phenyliso-propyl)adenosine (R-PIA), an adenosine A₁ receptor agonist, and U50 488H, a K₁-opioid receptor agonist, inhibited the stimulatory effects of β-adrenoceptor activation on electrically induced [Ca²⁺]i transients measured by a spectrofluorometric method with fura-2/AM as the calcium indicator. The effects of these two agonists were blocked by their respective antagonists, namely 8-cyclopentyl-l,3-diprolxanthine and norbinaltorphimine. 3. The inhibitory actions of both R-PIA and U50488H on β-adrenoceptor augmentation of electrically induce. [Ca²⁺]i transients in the heart were more significantly reduced in SHR than in WKY rats, suggesting the negative modulatory actions of endogenous substances on 3-adrenoceptors were impaired in SHR, which may contribute to hypertension.     

CHROMOSOME 17q23: A LOCUS FOR CARDIOVASCULAR DISEASE

1. The gene for dipeptidyl carboxypeptidase 1 (angiotensin I-converting enzyme, kininase II; DCP1), located on chromosome 17q23, has been implicated in hypertension in rats. In humans associations have been found for the insertion allele of a bi-allelic insertion/deletion polymorphism of DCP1 with hypertension and the deletion allele with myocardial infarction. Other hypertension studies have, however, failed to find a relationship. 2. Mathematical predictions based on DCP1 association data suggest that high sib-pair numbers may be needed to achieve statistical significance by this approach, although differences in the severity of hypertension in different study groups could account for the disparate findings. 3. No association was found between DCP1 allele or genotype frequencies and obesity in essential hypertensives.     

The effects of prostaglandin E1 and sodium meclofenamate on blood pressure in renal hypertensive rats

Conflicting evidence exists regarding the ability of PGE₁ to normalize blood pressure in renal hypertensive rats. We performed experiments to determine the effect of PGE₁ (15 μg/kg i.p. daily for 3 weeks) in renal hypertensive Wistars and found no significant change in systolic pressure. A higher dose (150 μg/kg i.p.) lowered pressure after 14 days of treatment, but not back to control levels. Further investigations are required to establish the mechanism whereby PGE₁ evokes this fall.To test the hypothesis that endogenous prostaglandins have a hypotensive function in renal hypertension, experiments were performed using sodium meclofenamate to inhibit prostaglandin biosynthesis. In chronic hypertensive rats the drug had no significant effect, while in the acute phase of renal hypertension there was a dose-dependent inhibition of the pressure rise. The possibility is suggesteed that prostaglandins may initiate or sustain the acute phase of renal hypertension in rats.     

Selenium suppresses the metabolism of benzo[a]pyrene by rat-liver extracts,and exerts a dual effect on its mutagenicity

1. Liver homogenates from rats injected with 3 -methylcholanthrene were employed for metabolism of benzo[a]pyrene (BP) and in assays of aryl hydrocarbon hydroxylase (AHH) activity in vitro.

2. Sodium selenite inhibited AHH activity to a maximum of ～70%. It suppressed the overall metabolism of benzo[a]pyrene; a distinct reduction in the products was evident on h.p.l.c. analysis.

3. Sodium thiosulphate also inhibited AHH activity by ～ 47%. Inclusion of S₂O^2-₃ and SeO^2-₃, in combination, led to a cumulative inhibition of 87%.

4. The mutagenicity of BP in the Salmonella auxotroph reversion system (Ames test) was enhanced by SeO^2-₃ at concentrations below 0.2 mM. Above this level a significant anti-mutagenic effect was observed.     

Epistasis of the DRD2/ANKK1 Taq Ia and the BDNF Val66Met Polymorphism Impacts Novelty Seeking and Harm Avoidance

Mounting evidence from animal studies show that the mesolimbic dopaminergic pathways are modulated by the brain-derived neurotrophic factor (BDNF). This study investigates in N=768 healthy Caucasian participants the influence of two prominent functional single-nucleotide polymorphisms (SNPs) on the BDNF gene (BDNF Val66Met SNP) and the ankyrin repeat and kinase domain containing 1 (ANKK1) gene (DRD2 Taq Ia/ANKK1 SNP) on the personality traits of Novelty Seeking and Harm Avoidance, which are mediated, in part, through dopaminergic mesolimbic circuitry. Carriers of the 66Met+/A1+ variant scored lowest on Novelty Seeking and highest on Harm Avoidance, compared to all other genotype groups. These participants are characterized by a relatively low D₂ receptor density in the striatum and an impaired activity-dependent secretion of BDNF. This is one of the first genetic association studies to show a modulatory role for BDNF genetic variation on genetically mediated differences in the mesolimbic dopaminergic system in the context of human personality.     

Two pairs of phenylpropanoid enantiomers from the leaves of Eucommia ulmoides

Abstract

Two pairs of phenylpropanoid enantiomers, (+)-(7S,8S)-alatusol D (1a), (?)-(7R,8R)-alatusol D (1b), (?)-(7S,8R)-alatusol D (2a) and (+)-(7R,8S)-alatusol D (2b) were isolated from the leaves of Eucommia ulmoides Oliver. Among them, 1a and 2b were firstly obtained by chiral enantiomeric resolution. Their structures were elucidated based on extensive spectroscopic analysis and the induced CD (ICD) spectrum caused by adding Mo₂(AcO)₄ in DMSO. All compounds were tested on Hep G2 tumor cell lines. However, none of the compounds showed potential cytotoxic activity against Hep G2 in vitro.     

MELATONIN REDUCES BLOOD PRESSURE IN RATS WITH STRESS-INDUCED HYPERTENSION VIA GABAA RECEPTORS

• 1 Several groups have reported that melatonin produces a significant decrease in blood pressure in mammals and that pinealectomy in rats causes hypertension. The purpose of the present study was to investigate the effects of melatonin and bicuculline methiodide on the blood pressure of rats, both in the developing and fully developed stage of stress‐induced hypertension (SIH).
• 2 Rats with SIH were generated by mild electric foot shocks for 15 days, after which tail arterial systolic pressure and plasma angiotensin (Ang) II levels were measured. The effects of melatonin injections (i.p. or i.c.v.) on mean arterial pressure (MAP) in rats with SIH were also determined.
• 3 Pretreatment with 1 mg/kg, i.p., melatonin significantly diminished the elevated tail arterial systolic pressure and plasma AngII levels caused by 15 days stress. The suppressive effects of melatonin were blocked by i.p. injection of 1 mg/kg bicuculline methiodide, an antagonist of the GABA_A receptor.
• 4 Intraperitoneal (0.2, 0.5 and 1 mg/kg) or i.c.v. (0.15 and 1.5 µg/3 µL) injection of melatonin produced a dose‐dependent lowering of MAP in rats with SIH. The antihypertensive response induced by melatonin was blocked by injection of both 1 mg/kg, i.p., and 1.5 × 10⁶ µg/3 µL, i.c.v., bicuculline methiodide.
• 5 In conclusion, melatonin not only prevents increases in blood pressure during the developing stage of SIH, but can also reduce the blood pressure of rats that have already developed SIH. The antihypertensive effect of melatonin may be mediated by GABA_A receptors through inhibition of plasma AngII levels.

     

Effect of pretreatment with cadmium/cysteine or metallothionein on accumulation of cadmium challenged with either complexes

The effect of pretreatment with cadmium (Cd) complexes on the distribution and accumulation of Cd in the liver and kidneys was examined for the Cd complexes that are reabsorbed site-selectively at the renal proximal tubules of rats. Cd was administered simultaneously with excess cysteine or as metallothionein (MT) and then challenged by either complex, the former complex being reabsorbed preferentially at the S₃ segment of proximal tubules of the outer stripe of the outer medullary zone, while the latter complex was reabsorbed at the S₁ + S₂ segments of proximal tubules. Cd in the kidneys was increased by pretreatment with either complex. On the other hand, pretreatment reduced the distribution of Cd to the liver. However, no site-selective effects were observed with either complexes. Calcium concentration, which was elevated significantly in the kidneys by a single injection of both complexes, was reduced by pretreatment.     

Effects of Ageing on the Oral Absorption of d-Xylose in Rats: Analysis of Gastrointestinal Disposition

The effects of ageing on the oral (gastrointestinal) absorption of d -xylose were investigated by analysing the gastrointestinal disposition after oral administration to young (9 weeks) and old (53 weeks) rats. A linear model assuming first-order gastric emptying followed by first-order intestinal absorption was fitted to remaining fraction vs time profiles for the stomach and small intestine to estimate the gastric emptying rate constant (k_g) and the intestinal absorption rate constant (k_a). In young and old rats, k_g values were 0·087 ± 0·008 and 0·070 ± 0·007 min^?1, respectively, and k_a values were 0·020 ± 0·002 and 0·018 ± 0·002 min^?1 suggesting an insignificant effect on ageing on the rate of oral absorption. The average intestinal lumen volume (V_av) was unchanged with ageing, and so was the apparent intestinal membrane permeability clearance (CL_app) as the product of k_a and V_av. However, the small intestinal transit time (T_si) was suggested to be twice that in older rats (171 min) than in young rats (78 min) by the analysis of gastrointestinal disposition of inulin, a non-absorbable marker. It was also shown that our preceding finding of an increase in the fraction absorbed of D-xylose with ageing can be solely ascribable to the delay in intestinal transit. Thus, among various determinants of oral absorption, only T_si was found to be altered with ageing. The CL_a,app and k_a of passively absorbed drugs such as D-xylose may be generally unchanged, and the fraction absorbed may increase with ageing by the delay in intestinal transit.