Michaelis-menten absorption kinetics in drugs: — Examples and implications

Summary It is shown that the absorption of phenylbutazone, naproxen, and chlorthiazide is governed by a dose limiting mechanism. This dose dependency may be explained by a saturation absorption process mathematically obeying Michaelis-Menten type kinetics. Observed dose relationships for tetracycline, fenclozic acid and related compounds, phenytoin, and possibly digoxin and digitoxin may be explained if a saturable process in absorption is postulated. This behavior may be produced by insolubility of the drug compound, a limited window of absorption in the gastrointestinal tract, or a capacity limited absorption because of the carrier or the transport mechanism involved. The need for suitably designed dose response studies with new drug compounds is discussed.     

Dose-Dependent Intestinal Absorption and Significant Intestinal Excretion (Exsorption) of the β-Blocker Pafenolol in the Rat

The elimination of [³H]pafenolol and metabolites was investigated in fasted and fed rats. Separate groups received intravenous doses (0.3 and 3.0 µmol/kg) and oral doses (1 and 25 µmol/kg). After iv administration of pafenolol, the excretion of unchanged drug into urine and feces was about 50 and 25–30% of the given dose, respectively. The predominating mechanism for the excretion of pafenolol into feces was intestinal excretion (exsorption) directly from blood into gut lumen, since only about 3% of a given iv dose was recovered as pafenolol in the bile. When the oral dose was raised from 1 to 25 µmol/kg, the mean (±SD) bioavailability, calculated from urine data, increased from 14 ± 9 to 30 ± 11% (P < 0.05) in the starved rats and from 14 ± 3 to 16 ± 3% in the fed animals. In parallel, the fraction absorbed from the gut (f _a) increased from 19 ± 9 to 31 ± 10% in the starved rats and from 16 ± 4 to 19 ± 5% in the fed animals, respectively. This indicates that the low bioavailability is due primarily to poor intestinal uptake.     

In vitro response of a human colon tumor xenograft and a lung adenocarcinoma cell line to alpha-difluoromethylornithine alone and in combination with 5-fluorouracil and doxorubicin

We have investigated effects of alpha-difluoromethylornithine (DFMO), both as a single agent and in combination with 5-fluorouracil (5-FU) against a human colon tumor xenograft (T6) grown as primary tissue culture in serum-free medium and in combination with doxorubicin (DX) against a human lung adenocarcinoma cell line (A549). DFMO showed a dose-dependent growth-inhibitory effect against human colon tumor xenograft and lung adenocarcinoma cells. Growth-inhibitory activity of DFMO against T6 cells was reversed completely when the cells were treated simultaneously with putrescine (PU) (10(-6) M) and DFMO (10(-3) M). When 5-FU and DFMO were used in combination against T6 cells, no antagonism or synergism between the two drugs was seen. However, in the case of A549 cells, when DFMO was used in combination with DX, there was a consistent increase in growth inhibition that surpassed the inhibition of either agent given alone.     

Effects of expanded human adipose tissue-derived mesenchymal stem cells on the viability of cryopreserved fat grafts in the nude mouse

Adipose-derived mesenchymal stem cells (AdMSCs) augment the ability to contribute to microvascular remodeling in vivo and to modulate vascular stability in fresh fat grafts. Although cryopreserved adipose tissue is frequently used for soft tissue augmentation, the viability of the fat graft is poor. The effects of culture-expanded human adipose tissue-derived mesenchymal stem cells (hAdMSCs) on the survival and quality of the cryopreserved fat graft were determined. hAdMSCs from the same donor were mixed with fat tissues cryopreserved at -70 °C for 8 weeks and injected subcutaneously into 6-week-old BALB/c-nu nude mice. Graft volume and weight were measured, and histology was evaluated 4 and 15 weeks post-transplantation. The hAdMSC-treated group showed significantly enhanced graft volume and weight. The histological evaluation demonstrated significantly better fat cell integrity compared with the vehicle-treated control 4 weeks post-transplantation. No significant difference in graft weight, volume, or histological parameters was found among the groups 15 weeks post-transplantation. The hAdMSCs enhanced the survival and quality of transplanted cryopreserved fat tissues. Cultured and expanded hAdMSCs have reconstructive capacity in cryopreserved fat grafting by increasing the number of stem cells.     

Dose-dependent kinetics of ethotoin in man

• 1 A gas-chromatographic assay for the anticonvulsant drug ethotoin in plasma has been used to establish a kinetic basis for therapy in eight newly diagnosed epileptic patients.
• 2 Only a small fraction of ethotoin was excreted unchanged. Elimination curves were only rectilinear below a plasma concentration of 8 mg/l. During constant medication plasma concentrations tended to decrease in the first week. Steady-state plasma levels varied considerably between individuals. For all patients the plasma concentration/dose ratio increased with increasing dose.
• 3 Most of the results point to dose-dependent elimination kinetics in the therapeutic range and parallel what is known for phenytoin. Control of therapy by measurement of plasma levels of ethotoin is accordingly advocated.

     

Safety and toxicological evaluation of a novel chromium(III) dinicocysteinate complex

Chromium(III) is an essential trace element required for normal protein, fat and carbohydrate metabolism. It also helps in energy production and increasing lean body mass. Chromium(III) dinicocysteinate (CDNC) is a unique form of bioavailable chromium(III). This study was focused on determining the broad spectrum safety of CDNC. Acute oral, acute dermal, primary dermal and eye irritation studies, Ames’ bacterial reverse mutation assay, mammalian erythrocyte micronucleus test, and a 90-day dose-dependent oral toxicity study were conducted. Acute oral and dermal LD₅₀ of CDNC was found to be greater than 2000?mg/kg in Sprague-Dawley rats. A primary skin irritation study in New Zealand Albino rabbits demonstrated CDNC as slightly irritating. An eye irritation study exhibited that CDNC is moderately irritating. Ames’ bacterial reverse mutation assay and mammalian erythrocyte micronucleus test demonstrated CDNC as non-mutagenic. A dose-dependent 90-day oral toxicity study demonstrated no significant toxicity of CDNC. Body weight, food and water consumption, selected organ weights (expressed as percentages of body or brain weights), ocular health, hematology, blood chemistry, and histopathology showed no abnormal changes. Clinical and histopathological evaluation of CDNC identified a dose level of 5.7?mg/kg/day as the no observed adverse effect level (NOAEL). Overall, these results demonstrate the broad spectrum safety of CDNC.     

复方苦参碱对人增生性瘢痕成纤维细胞的抑制作用

目的:观察复方苦参碱对人增生性瘢痕成纤维细胞的抑制作用,为烧伤后增生性瘢痕的治疗提供实验依据。方法:体外培养烧伤后的人增生性瘢痕成纤维细胞,加入不同含量的复方苦参碱,24h后观察细胞形态学,以乳酸脱氢酶(lactatedehydroge-nase,LDH)为指标观察细胞毒性,用四甲基偶氮唑蓝(MTT)法检测其增殖活性。结果:不同含量的复方苦参碱均能改变成纤维细胞形态,抑制细胞增殖,含量在300mg/L以下无明显的细胞毒作用,EC50值约为20mg/L。结论:复方苦参碱对人增生性瘢痕成纤维细胞具有抑制作用,并呈剂量依赖关系,具有防治增生性瘢痕的应用前景。