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The combined effects of high doses of tetracycline and progesterone on parameters indicative for liver function (serum transaminases and urea, serum and liver triglycerides and cholesterol) have been studied in mice. Apart from disturbance of cholesterol metabolism tetracycline-induced liver dysfunction was not aggravated by progesterone.

By means of a newly developed high-pressure liquid chromatographic method the organ distribution of tetracycline (TC) and pyrrolidinomethyl-tetracycline (PMT) has been studied. When mice were treated with 50 mg/kg i.v. TC or PMT these antibiotics could be detected in all organs investigated (liver, kidney, heart, lung, muscle, spleen). Especially high concentrations were found in liver and kidneys, where TC and PMT could be detected up to 6 h. In animals treated with PMT part of the PMT applied decomposed slowly yielding TC, which was found together with PMT in blood and all organs.

In mice treated with 50 micrograms/g i.v. tetracycline (TC) or doxycycline (DC), respectively, drug concentrations have been measured in serum, whole blood, liver, kidneys, lungs, heart, skeletal muscle and bones. TC reached especially high concentrations in liver, kidneys and bones. DC was initially trapped by lung tissue and accumulated in liver and kidneys. Liver concentrations were higher for TC, kidney concentrations were higher for DC. In some tissues, e.g. liver and kidneys, TC and DC reached higher concentrations in females than in males.

The influence of tetracycline and doxycycline (10-100 micrograms/g i.v.) on the aggregational state of ribosomes from mouse liver was tested. Both drugs caused a disaggregation of the ribosomes as evidenced by a rise of the monosomes + disomes/polysomes ratio. Tetracycline was much more potent than doxycycline, the minimum effective doses for tetracycline being 10 micrograms/g i.v. as compared to 100 micrograms/g for doxycycline. The results show that tetracycline but not doxycycline at therapeutic dose range may interfere with the protein synthesis of the liver.

The effects of tetracycline and doxycycline (25 and 100 micrograms/g i.v.) on serum GOT, GPT, urea, bilirubin, cholesterol and triglycerides and on the hepatic cholesterol and triglyceride levels have been investigated comparatively in female mice of two age groups: young adult and old. Both tetracyclines caused increases in the serum transaminases and bilirubin and in the triglyceride and cholesterol contents of the liver that were less pronounced in old than in young adult mice. The reason for the age difference may be that doxycycline and tetracycline accumulated to a greater extent in the livers of the younger age group. Only the rise of the serum urea levels after tetracycline and doxycycline was greater in old mice than in the young adults.

The effects of tetracycline and doxycycline (10-100 mg/g i.v.) on the triglyceride and cholesterol contents of liver and blood were studied comparatively in male and female mice. Only tetracycline increased the triglyceride content of the liver. The cholesterol content of the liver was raised by both tetracycline and doxycycline. Tetracycline and doxycycline increased the concentration of unesterified cholesterol and decreased esterified and total cholesterol in the serum. Most effects were more consistent or more pronounced in females than in males.

A comparative study was made on the effects of tetracycline (TC), rolitetracycline (RTC), and doxycycline (DC) at doses of 10-100 micrograms/g i.v. on serum GOT, GPT, bilirubin and urea levels of male and female mice. All tetracyclines at doses of 50-100 micrograms/g caused an increase of serum GOT and GPT activities in females after 2-8 h. This effect was less pronounced in males. The serum urea levels were markedly raised by TC and DC (50-100 micrograms/g) and RTC (10-100 micrograms/g). This effect was produced only in females. It was long-lasting (up to 8 h) after TC and RTC and more transient after DC. Likewise the tetracyclines affected the serum bilirubin only in females but not in males. All tetracyclines (25-100 micrograms/g) increased the amount of unconjugated and total bilirubin. This effect was most pronounced after TC, which also reduced the level of conjugated bilirubin.

The combined effects of ethinyl estradiol (EE) (0.5 micrograms/g s.c. once daily for 4 days) and tetracycline (TC) or doxycycline (DC) (50 micrograms/g i.v.) on liver weight and water content, serum transaminases, alkaline phosphatase, urea, triglycerides, and cholesterol as parameters of various liver functions were investigated in mice. It became apparent that depending on the parameter tested synergistic and antagonistic effects may occur, e.g., synergistic effects were observed with the serum transaminases and liver cholesterol; antagonistic effects were seen with the serum urea and serum cholesterol.