Dennis Schneck
Pennsylvania State University
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Clinical Pharmacology & Therapeutics | 2004
Steven G. Simonson; Ali Raza; Paul Martin; Patrick D. Mitchell; John A. Jarcho; Colin D.A. Brown; Amy S. Windass; Dennis Schneck
Cyclosporine (INN, ciclosporin) increases the systemic exposure of all statins. Therefore rosuvastatin pharmacokinetic parameters were assessed in an open‐label trial involving stable heart transplant recipients (≥6 months after transplant) on an antirejection regimen including cyclosporine. Rosuvastatin has been shown to be a substrate for the human liver transporter organic anion transporting polypeptide C (OATP‐C). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. Therefore the effect of cyclosporine on rosuvastatin uptake by cells expressing OATP‐C was also examined.
Clinical Pharmacology & Therapeutics | 2004
Dennis Schneck; Bruce K. Birmingham; Julie Zalikowski; Patrick D. Mitchell; Yi Wang; Paul Martin; Kenneth C Lasseter; Colin D.A. Brown; Amy S. Windass; Ali Raza
Coadministration of statins and gemfibrozil is associated with an increased risk for myopathy, which may be due in part to a pharmacokinetic interaction. Therefore the effect of gemfibrozil on rosuvastatin pharmacokinetics was assessed in healthy volunteers. Rosuvastatin has been shown to be a substrate for the human hepatic uptake transporter organic anion transporter 2 (OATP2). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. The effect of gemfibrozil on rosuvastatin uptake by cells expressing OATP2 was also examined.
Journal of Chromatography B: Biomedical Sciences and Applications | 1979
J Frederick Pritchard; Dennis Schneck; Arthur H. Hayes
A method for the determination of propranolol and six of its metabolites, as well as their glucuronide and/or aryl sulfate conjugates in human urine is described. Propranolol and its basic and neutral metabolites are extracted into ether at pH 9.8, evaporated to dryness, reconstituted, separated on a reversed-phase, high-pressure liquid chromatographic system and quantitated using fluorescence detection. The aqueous urine aliquot is then made acidic and the acid metabolites extracted and measured using similar methods. The presence of 2% sodium metabisulfite in all urines collected is essential to ensure the stability of 4-hydroxy-propranolol during collection and storage. Preliminary data is presented from 24-h urine samples collected from three patients chronically receiving propranolol.
Clinical Pharmacology & Therapeutics | 1980
Dennis Schneck; J Frederick Pritchard; Thomas P Gibson; Jean E. Vary; Arthur Hull Hayes
The relationship between plasma levels of 4 propranolol metabolites—naphthoxylactic acid (NLA), 4‐hydroxypropranolol (4‐OH), naphthoxy acetic acid (NAA), and propranolol glycol (PG)—and propranolol plasma levels was determined in healthy, adult male subjects after increasing single oral doses of propranolol. NLA was present at plasma levels 6 to 25 times that of propranolol. More than 90% of circulating NLA was in the plasma fraction, where it was 95% protein bound. The ratio of plasma concentrations of the pharmacologically active metabolite 4‐OH to propranolol approached unity 0.5 hr after propranolol, 160 mg or 320 mg orally, but fell rapidly. Plasma levels of NAA were in the same range as propranolol, especially as time progressed. PG circulated at plasma levels less than 12% of propranolol. As oral doses of propranolol were increased from 20 to 320 mg, there was a decrease in intrinsic plasma clearance (Cli) from 425 to 200 l/hr. Half‐life rose from 3 to 5 hr. Urinary recovery of 4‐OH fell as Cli rose. Urinary recovery of propranolol conjugates, NLA, and N‐desisopropylpropranolol (NDIPP) rose as Cli fell. Our results suggest that naphthalene ring oxidation of propranolol represents a high‐affinity low‐capacity enzymatic pathway(s) that plays an important role in the extensive hepatic extraction of propranolol after small doses orally. Plasma NLA and plasma NAA were determined before and after hemodialysis in 14 uremic patients receiving long‐term propranolol therapy. Mean plasma NLA was 4,372 ng/ml, and mean plasma NAA level was 238 ng/ml when mean plasma propranolol level was 15 ng/ml.
Clinical Pharmacology & Therapeutics | 1984
Dennis Schneck; Jean E. Vary
Five healthy subjects were given oral 14C‐propranolol (10 µCi, 40 mg) alone and in combination with hydralazine, 25 and 50 mg. Hydralazine increased propranolol peak concentrations from 25 ±7 ng/ml to 61 ± 10 and 85 ± 11 ng/ml, reduced time to peak concentrations from 2.2 ± 0.2 hr to 0.7 ±0.1 and 0.8 ±0.1 hr, and increased area under the propranolol concentration : time curves from 153 ±38 ng · ml−1 · hr to 246 ± 64 and 324 ng · ml−1 · hr (in all cases P < 0.05). Hydralazine did not change the fraction of the 14C‐propranolol dose recovered in the urine as basic, acidic, and polar metabolites: 0.28 ± 0.02, 0.27 ± 0.03, and 0.44 ± 0.03. The urinary excretion rate of radioactive metabolites of propranolol in acid, basic, and residue fractions increased in the 0 = to = 2‐hr time interval after hydralazine but there was no change in the relative proportion of each metabolite fraction at any time. Similar results were obtained by HPLC. Studies with radioactive propranolol indicate that a major acid and basic metabolite remains to be defined in addition to unextracted polar metabolites. Our data indicate that hydralazine increases propranolol bioavailability by its hemodynamic actions rather than by inhibition of its metabolism.
Clinical Pharmacology & Therapeutics | 1978
Dennis Schneck; Jeffrey S. Sprouse; Kenneth L. Miller; Jean E. Vary; Floyd O. DeWitt; Arthur Hull Hayes
The steady‐state plasma levels of unchanged free (H) and its ALC were measured in 6 normal volunteers—3 RA and 3 SA. All subjects received 25 mg H every 6 hr for a total of 12 doses; RA received an additional dose of 50 mg in a similar manner. Peak plasma levels offree H occurred at ½ to 1 hr following drug administration and declined with a t½ of 3.5 to 4.5 hr in both RA and SA. In contrast, ALC levels remained approximately constant over the 8‐hr sampling period. In the SA the mean steady‐state plasma concentration of ALC was 28% of the free H at the 25‐mg dose level. In the RA the percentages were 25 at the 25‐mg dose and 22 at the 50‐mg dose. These results indicate that under steady‐state conditions H is present predominantly in its free form. Administration of H (12 doses; 25 or 50 mg every 6 hr) with PA (every 3 or 4 hr) resulted in no alteration in the plasma levels of either H and its ALC or PA and its acetylated metabolite. This remained true when each phenotype was considered separately. The results from this portion of the study demonstrate that in normal subjects therapeutic plasma levels of neither PA nor H interfere with the acetylation of the other. Possible explanations for the lack of an interaction are presented.
Archive | 2007
ja sellise koostise kasutamine induktorit v i substraati; Ali Raza; John Stuart Pears; Howard Gerard Hutchinson; Dennis Schneck; Takahiko Baba; Akira Touchi; Yoshitaka Yamaguchi
Archive | 2005
Ali Raza; Stuart Pears John; Gerard Hutchinson Howard; Dennis Schneck; Takahiko Baba; Akira Touchi; Yoshitaka Yamaguchi
Archive | 2000
Takahiko Baba; Howard Gerard Hutchinson; John Stuart Pears; Ali Raza; Dennis Schneck; Akira Touchi; Yoshitaka Yamaguchi
Archive | 2000
Takahiko Baba; Howard Gerard Hutchinson; John Stuart Pears; Ali Raza; Dennis Schneck; Akira Touchi; Yoshitaka Yamaguchi