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published_or_final_version / Pharmacology / Master / Master of Philosophy

The influence of vitamin C on the pharmacokinetics of caffeine was investigated in ten elderly males, age 66 to 86 years. Caffeine (4 mg kg⁻¹) was administered intravenously on three different occasions over a seven-week period: before vitamin C restriction, after approximately four weeks of vitamin C restriction (15 mg dietary intake per day), and after two weeks of vitamin C supplementation (500 mg orally, twice daily). Blood and urine samples were collected over a 48-hour period following each caffeine administration. The plasma half-life (t₁/₂), rate constant of elimination (K), apparent volume of distribution (V), total body clearance (TBC), renal clearance (RC), and metabolic clearance (MC) of caffeine were determined. Simultaneous plasma (PVC), whole blood (WBVC), and leukocyte (WBCVC) vitamin C concentrations were obtained. All of the mean vitamin C values determined at the first kinetic trial (KT-1) were within the normal ranges for the respective biologic fluid or tissue. All of the mean vitamin C values changed significantly during the study; decreasing to below the normal ranges by the second kinetic trial (KT-2) following dietary vitamin C restriction, and increasing to the normal ranges by the third kinetic trial (KT-3) following vitamin C supplementation. All of the decreases and increases in the individual and average vitamin C concentrations paralleled the observed decreases and increases in the daily vitamin C intake. None of the caffeine pharmacokinetic parameters evaluated changed significantly during the study. The mean rate constant of elimination was approximately 0.15 hr⁻¹, the average plasma half-life was approximately 4.5 hours, and the mean apparent volume of distribution was approximately 500 ml kg⁻¹ for all three kinetic trials. The average total body, renal, and metabolic clearances were approximately 76.9, 1.3, and 76.0 (ml hr⁻¹)kg⁻¹, respectively, for all three kinetic trials. With the exception of V and TBC, the various pharmacokinetic characteristics investigated were in general agreement with data reported for younger subjects. The average apparent volume of distribution determined at any of the kinetic trials was about 16% lower than the value reported for young, healthy subjects. Similarly, the mean total body clearance observed was about 21% lower than that observed in young, healthy subjects. Since the average elimination rate constant observed in these elderly subjects is similar to the values observed in younger subjects and since TBC is equal to the product of V times K, the reduced TBC observed in this study appears to be due to the reduction in V, rather than to a decrease in the intrinsic metabolic capacity of the liver with aging. No relationship between vitamin C intake and/or body levels and the pharmacokinetics of caffeine was observed. These results indicate that the elimination of caffeine in the elderly is not affected significantly by the concentrations of vitamin C achieved during the study.

Cyclic AMP-dependent protein kinase (cAMP-PK) is an important mediator of hormone action. Its activity ratio is an accurate indicator of cellular activity under various experimental conditions including: (1) age and sex, (2) hormone administration and (3) temperature and photoperiod. Pituitary activity in unstimulated birds is not altered by age, but thyroid activity is much higher in old birds than in young animals. Thyrotropin releasing hormone (TRH) increases pituitary, thyroid and liver activity of prepubescent chickens, but has no effect on aged males and increases only thyroid and liver activities in aged females, suggesting a reduction in pituitary-thyroid function with advancing age. In prepubertal females, TRH increases pituitary and thyroid cAMP-PK activity, plasma T₃ and T₄ levels and liver T₄ monodeiodination. Thyroid activity reaches maximum activity before the pituitary, while plasma T₄ and liver T₄ monodeodinating activity reach their highest levels 20 minutes before plasma T₃. These findings suggest that fluctuations in liver T₄ 5' monodeiodinating activity might be responsible for the cyclic response of plasma T₃ and T₄. Castrated cockerels have larger pituitaries than untreated birds, but contain the same amount of DNA. Methimazole-fed cockerels have pituitaries significantly smaller than controls, while castrated cockerels fed methimazole have pituitaries the same size as untreated birds. Pituitary DNA is less than controls in both groups of methimazole-fed birds. These results are considered to be due to a change in the thyrotroph population, without an increase in total cell numbers, and may indicate a transformation of basophils. Pituitary cAMP-PK activity during cold stress substantiates this conclusion. Thyroid glands of castrated and untreated cockerels are smaller in size, histological appearance and DNA content; however, cAMP-PK activity is much greater in the castrated birds. Methimazole-fed cockerels have enlarged thyroid glands, elevated cAMP-PK activity, increased DNA and cellular hypertrophy; however, these effects may be mitigated by castration. Seven days after removal of testosterone supplements, photostimulated castrates have a higher thyroid cAMP-PK activity ratio than short day castrates; however, both groups are elevated above control, suggesting that long photoperiods enhance the stimulatory effects of castration on thyroid activity. Pituitary activity is elevated in long and short day birds seven days after removal of testosterone, but remains high only in short day castrates. Therefore, a reduction in the sensitivity of the hypothalamic-pituitary axis to testosterone may occur only in long day cockerels.

No description available.