The effects of liver disease on the pharmacokinetics and protein binding of cefazolin and cephalothin were studied in patients with cirrhosis, chronic active hepatitis or normal liver function. The T1/2 and mean residence time of cefazolin were significantly shorter in cirrhosis. Cephalothin clearance was decreased by cirrhosis. Plasma protein binding of cefazolin, but not cephalothin was significantly reduced in cirrhosis. It is suggested that no dose reduction is necessary for either drug in severe hepatic impairment.

ABSTRACT:MKC-963, (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine, a potent inhibitor of platelet aggregation, was synthesized and used in clinical trials in the 1990s. In the process of clinical study, it was found that urinary excretion ratios for 6␤-hydroxycortisol and free cortisol increased significantly in parallel with decreases in the plasma concentrations of MKC-963 after repeated oral administration of the compound to healthy volunteers. These findings suggested that MKC-963 caused autoinduction (defined as the ability of a drug to induce enzymes that enhance its own metabolism, resulting in dispositional tolerance) in humans, and clinical studies using the compound were stopped. This experience prompted us to reevaluate the effects of this compound on CYP3A4 using primary human hepatocytes and cDNA-expressed human cytochrome P450 (P450) enzymes to determine whether the autoinduction of MKC-963 metabolism in humans could have been predicted if these in vitro systems had been used for the evaluation of MKC-963 in the preclinical study. The results of in vitro study showed that MKC-963 increased CYP3A4 mRNA expression level and activity of testosterone 6␤-hydroxylation to extents similar to those observed with rifampicin in primary human hepatocytes. In addition, approximately 90% of the MKC-963 metabolism in human liver microsomes was estimated to be attributable to CYP3A4. These in vitro findings are in good agreement with the results of clinical study, suggesting that studies using human hepatocytes and cDNA-expressed human P450s are useful for assessing the autoinductive nature of compounds under development before starting clinical studies. (Fig. 1), a potent inhibitor of platelet aggregation, was synthesized and used in clinical trials by Mitsubishi Chemical Corp. (Tokyo, Japan) in the 1990s. In the process of clinical trials, the urinary excretion of 6␤-hydroxycortisol (6␤-OHF) and free cortisol (F) was studied after repeated oral administration of MKC-963 in human volunteers to determine whether this compound induces CYP3A4 or not. This was because the compound would be used for treatment of circulatory disorders together with drugs such as antihypertensives, antihyperlipidemics or antidiabetes. Many of these drugs are metabolized by CYP3A4 (Li et al., 1995;Lehmann et al., 1998;Prueksaritanont et al., 2003;Jerling et al., 2005), a predominant P450 enzyme found in the adult human liver that catalyzes the oxidation of a wide variety of exogenous compounds (Guengerich et al., 1986). In addition, CYP3A4 had been reported to be induced by several drugs, including rifampicin, phenytoin, and phenobarbital, that caused clinical drugdrug interactions (Holtbecker et al., 1996;Anderson 1998;Ridtitid et al., 2002). Moreover, measurement of the urinary ratio of 6␤-OHF and F (6␤-OHF/F) had been regarded as a safe and simple method for evaluating induction of CYP3A4 because it is noninvasive and does not require administration of a probe drug to volunteers (Galteau and Shamsa, 2003). MKC-963, (R)-1-(1-cycloh...

The physiological and pharmacological functions of the 20-kDa human GH (20K-hGH) isoform are unknown. We conducted a pharmacokinetic study of recombinant 20K-hGH in human subjects (Phase I clinical trial). Placebo or 20K-hGH was administered sc to normal men (20-31 yr of age, n = 6-8 per group) at 2100 h. Serum 20K- and 22K-hGH levels were monitored every 30 min for 24 h by specific enzyme-linked immunosorbent assays. Serum free fatty acid, insulin-like growth factor I, insulin, and glucose levels were measured for 24 h. In the placebo group, the secretion profiles of endogenous 20K- and 22K-hGH were pulsatile and similar to each other. The proportion of 20K- to 22K-hGH was fairly constant. In the 20K-hGH-treated groups, serum 20K-hGH levels increased in a dose-dependent manner over the dose range of 0.01-0.1 mg/kg. Maximum serum 20K-hGH levels were reached at 3-4 h and decreased with half-lives of 2-3 h. Marked suppression of endogenous 22K-hGH secretion was observed in a time-dependent manner. Serum free fatty acid and insulin-like growth factor I levels were significantly elevated (P < 0.01) at 4, 8, and 12 h and at 8, 12, and 24 h after 20K-hGH administration, respectively. Serum insulin and glucose levels did not change significantly within 24 h. These results suggested that: 1) regulation of 20K-hGH secretion is physiologically the same as that of 22K-hGH; 2) the pharmacokinetics after sc injection of 20K-hGH are comparable with those of 22K-hGH; 3) 20K-hGH regulates hGH secretion through "GH-induced negative feedback mechanisms"; and 4) administration of 20K-hGH is expected to exert GH actions (growth-promoting activity and lipolytic activity). Monitoring of serum 20K- and 22K-hGH levels may be useful in evaluating the effects of administered GH isoforms on their own release from the pituitary.

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