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Biomedical subjects

D D Shen

Publications and source records attributed to D D Shen.

103 records · Page 6Linked to original sources
PubMed1977

Theophylline bioavailability: a comparison of the oral absorption of a theophylline elixir and two combination theophylline tablets to intravenous aminophylline.

The bioavailability of theophylline from single doses of an elixir (Elixophyllin) and two different tablet formulations, as compared to intravenous aminophylline, was studied with a crossover design in 12 normal volunteers. Both tablet formulations (Marax and Tedral) contain ephedrine. Marax contains hydroxyzine hydrochloride, and Tedral contains phenobarbital. The absorption of theophylline was most rapid from the elixir, whereas that from Marax was faster than that from Tedral. The peak concentrations of theophylline after administration of the 3 oral dosage forms were in the order, elixir greater than Marax greater than Tedral, however, the time to achieve peak concentration was highly variable and did not differ significantly among the 3 products. On the basis of area under the serum concentration-time curves, the absorption of theophylline from the elixir and from Marax was essentially complete. The area under the serum concentration curve after administration of Tedral was significantly less than that after intravenous aminophylline, elixir, and Marax; however, when the individual areas under the concentration curves were adjusted for intrasubject variation in elimination rate constant, the mean area under the concentration curve after Tedral no longer differed significantly from those of the intravenous and other two oral products. A large degree of intersubject variation in the oral absorption of theophylline was observe din this study. Therefore, in addition to the well-documented, large individual variation in the serum clearance of theophylline, intersubject differences in the absorption of the drug is another factor that complicates proper adjustment of the dose in oral theophylline therapy.

Administration, Oral↗
PubMedDate not supplied

Disposition kinetics of disopyramide in patients with renal insufficiency.

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (beta) was related to the endogenous creatinine clearance (Clcr). However, a decrease in beta was not observed until the Clcr was reduced below 40 ml min-1. Below 40 ml min-1 a linear relationship existed between beta and Clcr. Similarly, the plasma elimination half-life (t 1/2 beta) showed a significant increase when the Clcr was less than 30 ml min-1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two-thirds of that in normal subjects. Therefore, in patients with Clcr less than 40 ml min-1 both the loading and maintenance dose of disopyramide should be reduced.

Arrhythmias, Cardiac↗
PubMedDate not supplied

Accumulation and washout kinetics of valproic acid and its active metabolites.

There is growing evidence that the metabolites of valproic acid (VPA) may be pharmacologically active and could contribute to both the therapeutic and toxic effects of the drug. The accumulation and washout kinetics of VPA and its oxidative metabolites were, therefore, examined in five healthy volunteers. Valproic acid (250-mg capsules) was administered bid for 15 days. Blood samples were obtained periodically during the 15 days of drug administration and for seven days following termination of treatment. Urine was also collected over the final dosing interval. Steady-state serum concentrations of VPA were achieved within three to four days of treatment. The accumulation of all metabolites in serum lagged behind that of the parent compound, with the mono-desaturated metabolites accumulating more slowly than the hydroxylated species. Furthermore, the apparent washout half-life of each metabolite was longer than the elimination half-life of VPA. In general, the unsaturated metabolites were eliminated more slowly than the hydroxylated metabolites. The serum and urinary metabolite profiles of VPA observed in the healthy volunteers were comparable with those reported for epileptic patients. The differences in the disposition kinetics of VPA and of its potentially active metabolites may explain the previously observed dissociation between the pharmacokinetics and pharmacodynamics of the drug in epileptic patients.

Adult↗
PubMedDate not supplied

Efficacy of stiripentol in the intravenous pentylenetetrazol infusion seizure model in the rat.

The potential effectiveness of stiripentol, a new allylic alcohol anticonvulsant, against generalized epilepsy of the absence type was evaluated in the intravenous pentylenetetrazol (PTZ) infusion seizure model in the rat. The ability of stiripentol to elevate the threshold dose of PTZ in eliciting clonic seizure (i.e., ratio of the post-drug threshold dose to the baseline threshold dose) was measured. Dose-response studies were performed after acute intraperitoneal injection and subacute oral drug treatment. Concentrations of stiripentol in plasma and whole brain were determined. Significant elevation in PTZ threshold dose was observed at a single 300 mg/kg intraperitoneal dose of stiripentol or at plasma levels exceeding 35 micrograms/ml. Maximal anticonvulsant response (i.e., a dose ratio of 3) was reached with doses at or above 450 mg/kg (or plasma concentration greater than or equal to 120 micrograms/ml), along with the appearance of neurotoxicity. Subacute treatment consisted of 9 consecutive oral doses of stiripentol over a 3 day period, until steady-state plasma stiripentol concentration was attained. Response data were obtained at dosage levels of 150, 400 and 800 mg/kg with respective mean steady-state levels of 33.2 +/- 7.8, 61.4 +/- 20.7, and 116 +/- 14 micrograms/ml. Maximal anticonvulsant effect was not reached even at the highest dose of 800 mg/kg. Correlation of threshold dose ratio with plasma and brain stiripentol concentrations showed an approximate 40% loss in anticonvulsant potency during subacute treatment. However, the animals also became more resistant to drug-induced neurotoxicity; about 40% higher plasma or brain stiripentol concentrations had to be reached for a given degree of neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Comparative pharmacodynamics and brain distribution of E-delta 2-valproate and valproate in rats.

The E-isomer of 2-unsaturated valproate (E-delta 2-VPA) is a pharmacologically active metabolite of VPA that is less teratogenic and hepatotoxic than its saturated precursor. To assess potential use of E-delta 2-VPA as an alternate to VPA, a dose-response study comparing the anticonvulsant activity and neurotoxicity of E-delta 2-VPA and VPA was conducted in rats using the intravenous (i.v.) pentylenetetrazol (PTZ)-infusion threshold seizure model. Assay of drug in whole brain and plasma allowed comparison of the drug concentration-effect relationships and the brain distribution characteristics of the two compounds. E-delta 2-VPA was two to three times more potent than VPA in elevating the clonic seizure threshold of PTZ, in reference to either plasma or whole-brain drug concentrations. Furthermore, much steeper response curves were observed with E-delta 2-VPA as compared with VPA. Within the pharmacologic concentration range (defined as EC25 to EC75), E-delta 2-VPA was less neurotoxic than VPA as assessed by behavioral tests. Therefore, E-delta 2-VPA has a much more favorable protective index than VPA. At low doses, the concentration ratios of brain to plasma for both E-delta 2-VPA and VPA increased markedly with increasing plasma drug concentration. E-delta 2-VPA and VPA were previously shown to exhibit saturable binding to rat plasma proteins. If we assume that uptake of drug into the CNS is limited to the equilibrium plasma free fraction in the brain microvasculature, much of the nonlinear brain distribution features of VPA could be accounted for by saturable drug plasma protein binding. On the other hand, more complex kinetics involving simultaneous saturation of plasma protein binding and blood-to-brain transport are proposed to explain the brain distribution of the unsaturated compound. In addition, the brain-to-free drug concentration ratios for both E-delta 2-VPA and VPA were below unity at high drug-concentration range, consistent with the presence of an efficient efflux mechanism of these compounds from brain.

Animals↗
PubMedDate not supplied

The effects of urine pH and plasma protein binding on the renal clearance of disopyramide.

To ascertain whether the renal clearance of disopyramide (pKa = 8.36) is affected by urine pH, the disposition kinetics of disopyramide were compared during excretion of acidic and alkaline urine following both single dose intravenous (2mg/kg) and oral (5 mg/kg) administration to 4 healthy male volunteers. No significant difference was observed in the plasma concentration-time curve of disopyramide. The mean 72 hour recovery of disopyramide and its N-deisopropyl metabolite (MND) in urine was 55.1 and 20.3% of the dose respectively, with no apparent difference between the two routes of administration or pH of urine. Renal clearance of disopyramide was found to vary with time, which is partly the result of a concentration dependent change in plasma protein binding. The unbound fraction of drug in plasma varied from 0.32 to 0.72 between 0.4 to 4microgram/ml concentration. However, time-dependent change in renal clearance of disopyramide persists even after correction for plasma protein binding.

Administration, Oral↗
PubMedDate not supplied

Induction of salicyluric acid formation in rheumatoid arthritis patients treated with salicylates.

Average steady-state serum salicylate concentrations and salicyluric acid (SU) formation rates were measured in 4 subjects with rheumatoid arthritis. After a salicylate washout period (1 month), the mean observed maximum formation rate of SU was determined by collecting frequent urine samples after a single oral dose of salicylate (35 mg/kg). The patients were then commenced on appropriate high dose salicylate therapy. Two and 5 weeks later, the mean observed maximum rates of SU formation were re-determined along with the average steady-state serum salicylate concentrations. Mean observed maximum SU excretion rates increased significantly between the single-dose study (0.96 +/- 0.22 mg/kg/h) and the last dose of the high dose therapy at 2 weeks (1.65 +/- 0.30 mg/kg/h; p less than 0.01); however, there was no further increase at week 5. Similar increases in the theoretical maximum rate of SU formation (Vmax) were observed between the single-dose study and after 2 weeks of high dose salicylate therapy. Average steady-state serum salicylate concentrations showed no decline between weeks 2 and 5. High dose salicylate therapy leads to acceleration of the rate of SU formation in patients with rheumatoid arthritis and this occurs largely during the first 2 weeks of therapy.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Pharmacokinetic interaction between verapamil and metoprolol in the dog. Stereochemical aspects.

The effect of verapamil co-administration on the hepatic first-pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium-labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first-pass effect of metoprolol was completely abolished after co-administration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 +/- 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil co-administration (R/S ratio = 1.01 +/- 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil co-administration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil.

Administration, Oral↗
PubMedDate not supplied

A reversible clearance model for the enterohepatic circulation of drug and conjugate metabolite pair.

An analytic expression for the plasma clearance of a drug, which undergoes enterohepatic circulation (EHC) in intact form and in the form of a hydrolyzable conjugate metabolite, was derived based on a four-compartment model that features the three successive steps of the recycling cascade: biliary excretion, intestinal hydrolysis, and reabsorption. The kinetic equation consists of irreversible and partially reversible clearance terms. The irreversible terms represent the removal of drug from the systemic circulation in a unidirectional fashion, such as renal clearance and extraconjugative biotransformation pathways. The reversible terms represent the two recycle pathways: biliary excretion of the parent compound, and the formation of a conjugate metabolite and its subsequent excretion into bile. Mathematically, the reversible clearance terms can be resolved into the product of a net recycled fraction and an irreversible clearance estimate for either biliary excretion or conjugate formation. The net recycled fractions are, in turn, a function of the competitive kinetics of drug or drug conjugate at each step of the EHC cascade. The derived clearance equation provides a useful conceptual framework in the kinetic analysis of factors controlling the reversibility of plasma drug clearance as a result of EHC. Analysis of the model also points to the development of new experimental strategies in elucidating the EHC of xenobiotics.

Bile↗
PubMedDate not supplied

Metabolic kinetics of pseudoracemic propranolol in human liver microsomes. Enantioselectivity and quinidine inhibition.

The enantioselective formation kinetics of 4-hydroxypropranolol (4-HOP), 5-hydroxypropranolol (5-HOP), and desisopropylpropranolol (DIP) were characterized over a wide substrate concentration range (1-1000 microM) in human liver microsomes using deuterium-labeled pseudoracemic propranolol. Existing data suggest that several microsomal cytochrome P-450 enzymes are involved in the oxidative metabolism of propranolol in humans. Biphasic kinetics were observed in the formation of all three metabolites, indicating the involvement of at least two enzymes in each pathway. The R/S ratios for the formation of all three metabolites varied with respect to the substrate concentration, lending further support to the contribution of two or more enzymes with differing KM's and enantioselectivity. The high-affinity 4-hydroxylation process showed a strong R-enantioselectivity. The low-affinity component of 4-hydroxylation also exhibited a preference for R-(+)-propranolol, although to a lesser degree than the high-affinity component. A similar pattern of enantioselectivity was observed for 5-hydroxylation, except that R/S ratio showed an initial increase followed by a decrease as the propranolol concentration increased beyond 200 microM. Formation of DIP was R-enantioselective at low substrate concentrations, whereas an opposite enantioselectivity was observed at high propranolol concentrations. The metabolism of propranolol in the presence of nanomolar concentrations of quinidine (a selective inhibitor of P-450 2D6) was studied at concentrations of pseudoracemic propranolol in the high- and low-affinity regions. A significant inhibition of 4- and 5-hydroxylation was observed, whereas N-dealkylation was not affected by quinidine. The inhibition of 4-hydroxylation was slightly enantioselective toward R-enantiomer. Quinidine had no significant effect on the low-affinity component for 4-hydroxylation. Although the inhibition of 4- and 5-hydroxylation at the high-affinity site was extensive, complete inhibition was not achieved even at the highest quinidine concentration (10 microM). Data could be fitted to a mixed-type inhibition kinetics resulting from multiple high-affinity hydroxylases. Our in vitro results indicate that formation of 4-HOP and 5-HOP is mediated by more than one P-450 enzyme with major contribution from P-450 2D6, whereas the formation of DIP is catalyzed by two or more P-450 enzymes other than 2D6.

Biotransformation↗
PubMedDate not supplied

Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes.

In an effort to investigate the metabolic basis of previously reported pharmacokinetic interactions between beta-adrenergic antagonists and calcium channel blockers, the effects of verapamil on the oxidative metabolism of metoprolol were studied in microsomes isolated from four human livers. Deuterium-labeled pseudoracemic metoprolol was used to characterize the substrate stereoselectivity of this metabolic interaction. Biphasic kinetics were observed for both the alpha-hydroxylation and O-demethylation of metoprolol, suggesting that multiple P-450 enzymes with differing KMs are involved in the formation of these oxidative metabolites. alpha-Hydroxylation showed a slight preference for S-(-)-metoprolol, and it was largely mediated by a high-affinity enzyme over a wide range of substrate concentrations. The high-affinity component of the O-demethylation reaction exhibited significant selectivity for the R-(+)-enantiomer. The opposite enantioselectivity was observed for the low-affinity component of O-demethylation. Racemic verapamil inhibited both the alpha-hydroxylation and the O-demethylation of metoprolol. The kinetics of inhibition were consistent with competitive effects of verapamil on the high-affinity components of both oxidative pathways, which previously had been suggested to be mediated by CYP2D6. Potent inhibition of the low-affinity component of O-demethylation was also observed. The inhibitory effect of verapamil on the alpha-hydroxylation of metoprolol was not enantioselective. On the other hand, verapamil preferentially inhibited the O-demethylation of R-(+)-metoprolol compared with S-(-)-metoprolol at low substrate concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytochrome P-450 Enzyme System↗